3,4,5-Trisubstituted-1,2,4-Triazoles and 3,4,5-Trisubstituted-3-Thio-1,2,4-Triazoles and Uses Thereof

ABSTRACT

The present disclosure describes novel compounds that are somatostatin receptor type 4 agonists.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.16/613,086, filed Nov. 12, 2019, which is the U.S. 371 National StageApplication of PCT/US2018/032368, filed May 11, 2018, which claimsbenefit of U.S. Provisional Application 62/505,384, filed May 12, 2017,the contents of which are incorporated herein by reference.

GOVERNMENTAL RIGHTS

This invention was made with government support under grant numberAG047858 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

TECHNICAL FIELD

The present disclosure relates to compounds that are somatostatinreceptor type 4 agonists.

BACKGROUND

Somatostatin, also known as somatostatin release inhibitory factor(SRIF) is a cyclic peptide distributed throughout the human body, and isinvolved in numerous physiological processes. SRIF occurs as atetradecapeptide and an N-terminally extended form (SST-28).

There are six somatostatin receptor (SSTR) subtypes; SSTR 1-5, includingthe alternatively spliced SSTR2A and SSTR2B receptors. The somatostatinreceptors were originally divided into two families based on bindingstudies with iodinated synthetic analogues of somatostatin; a highaffinity family (SRIF-1) and a lower affinity family (SRIF-2). When SRIFbinds to its receptors, it produces changes in intracellular signalingpathways. SSTRs are all G-protein coupled receptors (GPCRs). Throughreceptor action, SRIF produces primarily inhibitory effects on endocrineand exocrine secretions throughout the body, regulates cellulardifferentiation and proliferation, and acts as aneurotransmitter/neuromodulator in the central nervous system. GivenSRIF has shown to exhibit inhibitory actions on endocrine and exocrinesecretions, as well as numerous modulatory effects on neuronal activityin the periphery and central nervous system (CNS), the respectivereceptors have become primary therapeutic targets.

SUMMARY

One aspect of the disclosure encompasses a compound comprising FormulaI):

wherein

are independently a single bond or is absent;

A, B, and C are independently C, N, O, or S;

R¹ and R⁷ are independently hydrogen, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted fused ring system;

R² is substituted or unsubstituted C₁-C₆ alkyl;

R³, R⁴, and R⁵ are independently hydrogen, F, Cl, Br, I, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted amine, sulfoxide, sulfone, thiosulfinate, thiosulfonate,thioamide, sulfimide, sulfoximide, sulfonediimine, or sulfur halide;

R⁶ and R⁸ are independently hydrogen, F, Cl, Br, I, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedcycloalkyl; and

R⁹ is a substituted or unsubstituted C₁-C₃ alkyl;

with the proviso that when R⁹ is C₂ alkyl, R⁷ is not a3,4-dichlorobenzene; or a pharmaceutically acceptable salt thereof.

Another aspect of the disclosure encompasses a compound of Formula (II):

wherein

E are independently a bond or is absent;

A, B, and C are independently C, N, O, or S;

D is S, O, NR¹⁶, P, sulfone, or sulfoxide;

R¹ and R⁷ are independently hydrogen, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted cycloalkyl or substituted orunsubstituted fused ring system;

R² is substituted or unsubstituted C₁-C₆ alkyl;

R³, R⁴, and R⁵ are independently hydrogen, F, Cl, Br, I, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted amine, sulfoxide, sulfone, thiosulfinate, thiosulfonate,thioamide, sulfimide, sulfoximide, sulfonediimine, or sulfur halide;

R⁶ and R⁸ are independently hydrogen, F, Cl, Br, I, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedcycloalkyl;

R⁹ and R¹⁵ are independently substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, or substituted or unsubstituted cycloalkyl; and

R¹⁶ is hydrogen, C₁-C₆ alkyl, aryl, or benzyl;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

The present disclosure provides compounds of Formula (I) and Formula(II), which have been found to be somatostatin receptor type 4 agonists.

Various aspects of the disclosure are described in greater detail below.

I. Compounds of Formula (I)

Provided herein are compounds comprising Formula (I)

wherein

are independently a single bond or is absent;

A, B, and C are independently C, N, O, or S;

R¹ and R⁷ are independently hydrogen, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted fused ring system;

R² is substituted or unsubstituted C₁-C₆ alkyl;

R³, R⁴, and R⁵ are independently hydrogen, F, Cl, Br, I, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted amine, sulfoxide, sulfone, thiosulfinate, thiosulfonate,thioamide, sulfimide, sulfoximide, sulfonediimine, or sulfur halide;

R⁶ and R⁸ are independently hydrogen, F, Cl, Br, I, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedcycloalkyl; and

R⁹ is a substituted or unsubstituted C₁-C₃ alkyl;

with the proviso that when R⁹ is C₂ alkyl, R⁷ is not a3,4-dichlorobenzene; or a pharmaceutically acceptable salt thereof.

In one aspect, a compound of Formula (I) comprises any of the precedingcompounds of Formula (I), wherein

are each a single bond and A, B, and C are N.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R⁶ and R⁸ are independentlyhydrogen or substituted or unsubstituted C₁-C₃ alkyl.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R⁶ and R⁸ are hydrogen.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R⁶ and R⁸ are substituted orunsubstituted C₁-C₂ alkyl.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R¹ and R⁷ are independentlysubstituted or unsubstituted aryl or substituted or unsubstituted fusedring system.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R¹ is substituted orunsubstituted fused ring system.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R¹ is substituted orunsubstituted indole.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R⁹ is substituted orunsubstituted aryl.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R⁹ is

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R¹⁰, R¹¹, R¹², R¹³, and R¹⁴is independently hydrogen, F, Cl, Br, I, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedamine, sulfoxide, sulfone, thiosulfinate, thiosulfonate, thioamide,sulfimide, sulfoximide, sulfonediimine, or sulfur halide.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R¹⁰, R¹¹, R¹², R¹³, and R¹⁴is independently hydrogen, F, Cl, Br, I, CF₃, OCH₃, NO₂, OCH₂(C₆H₄),C₆H₄, SO₂CH₃, or OCF₃.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R² is substituted orunsubstituted C₁-C₃ alkyl.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R² is substituted orunsubstituted propyl.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R² is unsubstituted propyl.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R³, R⁴, and R⁵ areindependently hydrogen, F, Cl, Br, I, substituted or unsubstitutedalkyl.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R³, R⁴, and R⁵ are hydrogen.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R⁹ is methyl.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), wherein R⁹ is ethyl.

In another aspect, a compound of Formula (I) comprises any of thepreceding compounds of Formula (I), may be selected from the groupconsisting of:

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹² isfluoro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹¹, R¹², R¹³, and R¹⁴ are hydrogen; and R¹⁰ ischloro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; and R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹² ischloro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ ischloro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ is1-aminoethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; andR¹¹ is chloro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, and C are nitrogen; B is carbon; R¹ is 3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹² ischloro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³ and R¹⁴ are hydrogen; and R¹² ismethoxy.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ isbromo.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ isfluoro.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ istrifluoromethyl.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 1-methyl-3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ istrifluoromethyl.

In another aspect, a compound of the disclosure comprises Formula (I,wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ ismethoxy.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², and R¹⁴ are hydrogen; and R¹¹ and R¹³are chloro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 1-methyl-3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹³, and R¹⁴ are hydrogen; and R¹¹ and R¹²are chloro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹² isbenzyl.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ isoxomethylbenzene.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ issulfonylmethane.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ istrifluoromethoxy.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹¹, R¹², R¹³, and R¹⁴ are hydrogen; and R¹⁰ ismethoxy.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R1 is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R12, and R¹⁴ are hydrogen; and R11 and R¹³are fluoro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ isnitro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ isethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ iscyano.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹² ismethoxy.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 5-methoxy-3-indole; R²is propyl;

R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ is methyl; R⁷ isbenzene; R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹² is fluoro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 5-methoxy-3-indole; R²is propyl;

R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ is methyl; R⁷ isbenzene; R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 5-methoxy-3-indole; R²is propyl;

R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ is methyl; R⁷ isbenzene; R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹² is methoxy.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 5-methoxy-3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹¹ istrifluoromethyl.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 6-fluoro-3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹² isfluoro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 6-fluoro-3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³ and R¹⁴ are hydrogen; and R¹² ismethoxy.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 6-fluoro-3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is 6-fluoro-3-indole.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³ and R¹⁴ are hydrogen; and R¹² isfluoro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³ and R¹⁴ are hydrogen; and R¹² ischloro.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ istrifluoromethyl.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 6-fluoro-3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹¹ istrifluoromethyl.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 3-indole; R² ispropyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ issulfonylmethane.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 6-fluoro-3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 6-fluoro-3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is benzene; R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen; and R¹¹ isbromo.

In another aspect, a compound of the disclosure comprises Formula (I),wherein

are single bonds; A, B, and C are nitrogen; R¹ is 6-fluoro-3-indole; R²is propyl; R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen; R⁹ ismethyl; R⁷ is tert-butyl.

II. Compounds of Formula (II)

Also provided herein are compounds comprising Formula (II)

wherein

-   -   are independently a single bond or is absent;

A, B, and C are independently C, N, O, or S;

D is S, O, NR¹⁶, P, sulfone, or sulfoxide;

R¹ and R⁷ are independently hydrogen, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted cycloalkyl or substituted orunsubstituted fused ring system;

R² is substituted or unsubstituted C₁-C₆ alkyl;

R³, R⁴, and R⁵ are independently hydrogen, F, Cl, Br, I, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted amine, sulfoxide, sulfone, thiosulfinate, thiosulfonate,thioamide, sulfimide, sulfoximide, sulfonediimine, or sulfur halide.

R⁶ and R⁸ are independently hydrogen, F, Cl, Br, I, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedcycloalkyl;

R⁹ and R15 are independently substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, or substituted or unsubstituted cycloalkyl; and

R¹⁶ is hydrogen, C₁-C₆ alkyl, aryl, or benzyl;

or a pharmaceutically acceptable salt thereof.

In one aspect, a compound of Formula (II) comprises any of the precedingcompounds of Formula (II), wherein

are each a single bond and A, B, and C are N.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein D is S.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R⁹ is a bond.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹⁵ is unsubstituted C₁-C₃alkyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹⁵ is unsubstituted C₁-C₂alkyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R⁶ and R⁸ are independentlyhydrogen or substituted or unsubstituted C₁-C₃ alkyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R⁶ and R⁸ are hydrogen.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹ and R⁷ are independentlysubstituted or unsubstituted aryl or substituted or unsubstituted fusedring system.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹ is substituted orunsubstituted fused ring system.

In still another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹ is substituted orunsubstituted indole, substituted or unsubstituted naphthalene, orsubstituted or unsubstituted quinolone.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R⁷ is substituted orunsubstituted aryl or substituted or unsubstituted indole.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R⁷ is

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹⁰, R¹¹, R¹², R¹³, and R¹⁴is independently hydrogen, F, Cl, Br, I, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedamine, sulfoxide, sulfone, thiosulfinate, thiosulfonate, thioamide,sulfimide, sulfoximide, sulfonediimine, or sulfur halide.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹⁰, R¹¹, R¹², R¹³, and R¹⁴is independently hydrogen, F, Cl, Br, I, CF₃, OCH₃, NO₂, OCH₂(C₆H₄),C₆H₄, SO₂CH₃, or OCF₃.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R² is substituted orunsubstituted C₁-C₃ alkyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R² is substituted orunsubstituted propyl.

In yet another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R² is unsubstituted propyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R³, R³, and R⁴ areindependently hydrogen, F, Cl, Br, I, substituted or unsubstitutedalkyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R³, R³, and R⁴ arehydrogen.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), may be selected from the groupconsisting of.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is2-quinoline; R² is propyl; R³, R⁴, R⁵, R⁶ and R⁸ are hydrogen; R⁷ is3-indole; R⁹ is absent; R¹⁵ is ethyl; and R¹⁰, R¹¹, R¹², R¹³, and R¹⁴are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is2-naphthalene; R² is propyl; R³, R⁴, R⁵, R⁶ and R⁸ are hydrogen; R⁷ isbenzene; R⁹ is absent; R¹⁵ is methyl; and R¹⁰, R¹¹, R¹², R¹³, and R¹⁴are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is5-fluoro-3-indole; R² is propyl; R³, R⁴, R⁵, R⁶ and R⁸ are hydrogen; R⁷is benzene; R⁹ is absent; R¹⁵ is methyl; and R¹⁰, R¹¹, R¹², R¹³, and R¹⁴are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is1-naphthalene; R² is propyl; R³, R⁴, R⁵, R⁶ and R⁸ are hydrogen; R⁷ isbenzene; R⁹ is absent; R¹⁵ is methyl; and R¹⁰, R¹¹, R¹², R¹³, and R¹⁴are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl;

R³, R⁴, R⁵, R⁶ and R⁸ are hydrogen; R⁷ is benzene; R⁹ is absent; R¹⁵ ismethyl; and R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is aryl; R²is propyl; R³, R⁴, R⁵, R⁶ and R⁸ are hydrogen; R⁷ is benzene; R⁹ isabsent; R¹⁵ is methyl; and R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is3-methyloxy-aryl; R² is propyl; R¹⁵ is carbon; and R³, R⁴, R⁵, R⁶, R⁷,and R⁸ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 2-indole;R² is propyl;

R³, R⁴, and R⁵ are hydrogen; R⁷ is benzene; R⁹ is absent; R¹⁵ is methyl;and R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is benzene;R² is propyl; R¹⁵ is carbon; and R³, R⁴, R⁵, R⁶, R⁷, and R⁸ arehydrogen.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹² is an unsubstitutedC₁-C₃ alkyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹⁵ is unsubstituted C₁-C₆alkyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹⁵ is unsubstituted C₁-C₃alkyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R⁶ and R⁸ are independentlyhydrogen or substituted or unsubstituted C₁-C₃ alkyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R⁶ and Ware hydrogen.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹ and R⁷ are independentlysubstituted or unsubstituted aryl or substituted or unsubstituted fusedring system.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹ is substituted orunsubstituted fused ring system.

In still another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹ is substituted orunsubstituted indole.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R⁷ is substituted orunsubstituted aryl.

In still another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R⁷ is

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹⁰, R, R¹², R¹³, and R¹⁴is independently hydrogen, F, Cl, Br, I, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedamine, sulfoxide, sulfone, thiosulfinate, thiosulfonate, thioamide,sulfimide, sulfoximide, sulfonediimine, or sulfur halide.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R¹⁰, R, R¹², R¹³, and R¹⁴is independently hydrogen, F, Cl, Br, I, CF₃, OCH₃, NO₂, OCH₂(C₆H₄),C₆H₄, SO₂CH₃, or OCF₃.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R² is substituted orunsubstituted propyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R² is unsubstituted propyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R³, R³, and R⁴ areindependently hydrogen, F, Cl, Br, I, substituted or unsubstitutedalkyl.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), wherein R³, R³, and R⁴ arehydrogen.

In another aspect, a compound of Formula (II) comprises any of thepreceding compounds of Formula (II), may be selected from the groupconsisting of:

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is ethyl; R¹⁵ is methyl; R⁷ is benzene; and R¹⁰, R¹¹, R¹², R¹³, andR¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),use

wherein N are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is3-indole; R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ arehydrogen; R⁹ is ethyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰, R¹¹, R¹², andR¹⁴ are hydrogen; and R¹³ is chloro.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is ethyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰, R¹¹, R¹², and R¹⁴ arehydrogen; and R¹³ is fluoro.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is ethyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰, R¹¹, and R¹⁴ arehydrogen; and R¹² and R¹³ are chloro.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is benzene;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is ethyl; R¹⁵ is methyl; R⁷ is benzene; and R¹⁰, R, R¹², R¹³, and R¹⁴are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is methyl; R¹⁵ is methyl; R⁷ is benzene; and R¹⁰, R, R¹², R¹³, andR¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is methyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰, R¹¹, R¹², and R¹⁴ arehydrogen; and R¹³ is trifluoromethyl.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is methyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰, R¹¹, R¹², and R¹⁴ arehydrogen; and R¹³ is fluoro.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is methyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰, R¹¹, and R¹⁴ arehydrogen; and R¹⁵ and R¹³ chloro.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is methyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰, R¹¹, R¹², and R¹⁴ arehydrogen; and R¹³ is bromo.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is3-fluorobenzene; R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ andR⁸ are hydrogen; R⁹ is methyl; R¹⁵ is methyl; R⁷ is benzene; and R¹⁰,R¹¹, R¹², R¹³, and R¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is methyl; R¹⁵ is methyl; R⁷ is benzene; and R¹⁰, R¹¹, R¹², R¹³, andR¹⁴ are hydrogen.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is methyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰, R¹³, and R¹⁴ arehydrogen; and R¹¹ and R¹² is chloro.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and R⁸ are hydrogen;R⁹ is methyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³, and R¹⁴ arehydrogen; and R¹² is chloro.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is 3-indole;R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶ and Ware hydrogen; R⁹is methyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰, R¹¹, R¹³, and R¹⁴ arehydrogen; and R¹² is fluoro.

In another aspect, a compound of the disclosure comprises Formula (II),wherein are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is6-fluoro-3-indole; R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶,R⁷, and Ware absent; R⁹ is methyl; R¹⁵ is methyl; R⁷ is benzene; R¹⁰,R¹¹, R¹³, and R¹⁴ are hydrogen; and R¹² is fluoro.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is6-fluoro-3-indole; R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶,R⁷, and Ware absent; R⁹ is methyl; R¹⁵ is benzene; R¹⁰, R¹¹, R¹³, andR¹⁴ are hydrogen; and R¹² is methyl.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is6-fluoro-3-indole; R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶,R⁷, and Ware absent; R⁹ is methyl; R¹⁵ is benzene; R¹⁰, R¹², R¹³, andR¹⁴ are hydrogen; and R¹¹ is methoxy.

In another aspect, a compound of the disclosure comprises Formula (II),wherein

are single bonds; A, B, and C are nitrogen; D is sulfur; R¹ is6-fluoro-3-indole; R² is propyl; and R³, R⁴, and R⁵ are hydrogen; R⁶,R⁷, and R⁸ are absent; R⁹ is methyl; R¹⁵ is 5-pyridinyl.

It will be understood that depending upon the selection of certainsubstituents, certain compounds within the scope of general Formula (I)may be more readily synthesizable than other compounds also within thescope within Formula (I). Similarly, certain compounds within the scopeof general Formula (II) are more readily synthesizable than othercompounds also within the scope of general Formula (II). Art-recognizedprinciples and routine methods can be used for identifying the mostreadily synthesized compounds within the scope of the disclosure.

In another aspect, the present disclosure provides processes ofmanufacture of the novel compounds as disclosed herein, and of anyprodrug forms thereof.

In another aspect, the present disclosure provides a pharmaceuticallyacceptable salt, hydrate or solvate of any of the compounds disclosedherein, which are encompassed by general Formula (I) or Formula (II).Pharmaceutically acceptable salts include for example salts of inorganicor organic acids as well known in the art. Any compound of generalFormula (I) or Formula (II), or a pharmaceutically acceptable salt,hydrate, solvate or prodrug of any thereof, is optionally combined withone or more pharmaceutically acceptable carriers or excipients toprovide a pharmaceutical composition.

In another aspect, the present disclosure provides methods of using the3,4,5-trisubstituted-1,2,4-triazoles and3,4,5-trisubstituted-3-thio-1,2,4-triazole analogues disclosed herein assomatostatin receptor subtype-4 (SSTR4) agonists for use in theprevention and/or treatment of diseases or disorders related to SSTR4,e.g., disorders caused or influenced by activation of SSTR4. Suchdisorders include but are not limited to various forms of pain,including chronic, acute, visceral and neuropathic pain; andinflammation and inflammation-related disorders. Thus, any of the novelcompounds disclosed herein can be used as a medicament for the treatmentof pain, inflammation or inflammation-related disorders.Inflammation-related disorders include disorders of the cardiovascular,respiratory, gastrointestinal, nervous and skeletal systems whichinvolve inflammation. Such disorders include, for example,atherosclerosis; thrombosis; diseases of the lungs and airways such asasthma, bronchitis, chronic obstructive lung disease (COPD) andemphysema; diseases of the gastrointestinal system includingpancreatitis, Crohn's disease, irritable bowel syndrome, and ulcerativecolitis; diabetes-associated disorders such as diabetic nephropathy,neuropathy, retinopathy, and vasculopathy; disorders of the eyeincluding conjunctivitis, blepharitis, iritis, uveitis and glaucoma;disorders of skeletal joints and connective tissue including arthritisand back pain; diseases and disorders of the central nervous systemincluding epilepsy, dementia, Alzheimer's disease, learning disorders,neurodegenerative diseases such as Parkinson's Disease, multiplesclerosis, and amyotrophic lateral sclerosis, and psychiatric disorderssuch as anxiety and depression; morbid obesity; and cancer includingbenign and malignant tumors.

Any of the compounds of Formula (I) or Formula (II) are useful for theprevention and/or treatment of pain or inflammation, such as pain orinflammation associated with any one of the diseases or disordersdisclosed herein. According to the present disclosure, a method oftreatment for pain or inflammation comprises administering atherapeutically effective amount of a compound of Formula (I) or Formula(II) to a subject in need thereof. The subject is a mammal, for example,a human. A therapeutically effective amount of the compound of Formula(I) or Formula (II) will vary with the compound, the subject, the degreeand severity of the disorder being treated, and the route ofadministration, and can be readily determined according to guidancegenerally available to those of skill in the art, using routine methodsof optimization as needed. Usually an effective amount is a range ofabout 0.01 milligrams (mg) to about 100 mg/kilogram (kg) of body weightof the subject, which may be contained in a single dose or in dosesformulated for administration multiple (e.g., 2, 3 or 4) times per day.The therapeutically effective amount of the compound may be containedtogether with a pharmaceutically acceptable carrier or excipient in apharmaceutical composition as described herein.

Definitions

When introducing elements of the different aspects as described herein,the articles “a,” “an,” “the,” and “said” are intended to mean thatthere are one or more of the elements. The terms “comprising,”“including,” and “having” are intended to be inclusive and mean thatthere may be additional elements other than the listed elements.

As used herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, and the Handbook of Chemistry and Physics, 75th Ed. 1994.Additionally, general principles of organic chemistry are described in“Organic Chemistry,” Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5th Ed.,Smith, M. B. and March, J., eds. John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

“Alkyl” as used herein alone or as part of a group refers to saturatedmonovalent hydrocarbon radicals having straight or branched hydrocarbonchains or, in the event that at least 3 carbon atoms are present, cyclichydrocarbons or combinations thereof and contains 1 to 20 carbon atoms(C₁₋₂₀ alkyl), 1 to 10 carbon atoms (C₁₋₁₀ alkyl), 1 to 8 carbon atoms(C₁₋₈ alkyl), 1 to 6 carbon atoms (C₁₋₄ alkyl), or 1 to 4 carbon atoms(C₁₋₄ alkyl). Examples of alkyl radicals include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

“Alkenyl” as used herein alone or as part of a group refers tomonovalent hydrocarbon radicals having a straight or branchedhydrocarbon chains having one or more double bonds and containing from 2to about 18 carbon atoms, from 2 to about 8 carbon atoms, or from 2 toabout 5 carbon atoms. Examples of suitable alkenyl radicals includeethenyl, propenyl, alkyl, 1,4-butadienyl and the like.

“Alkynyl” as used herein alone or as part of a group refers tomonovalent hydrocarbon radicals having a straight or branchedhydrocarbon chains having one or more triple bonds and containing from 2to about 10 carbon atoms, or from 2 to about 5 carbon atoms. Examples ofalkynyl radicals include ethynyl, propynyl, (propargyl), butynyl and thelike.

“Aryl” as used herein, alone or as part of a group, includes an organicradical derived from an aromatic hydrocarbon by removal of one hydrogen,and includes monocyclic and polycyclic radicals, such as phenyl,biphenyl, naphthyl.

“Alkoxy” as used herein, alone or as part of a group, refers to an alkylether radical wherein the term alkyl is as defined above. Examples ofalkyl ether radical include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

“Cycloalkyl” as used herein, alone or in combination, means a saturatedor partially saturated monocyclic, bicyclic or tricyclic alkyl radicalwherein each cyclic moiety contains from 3 to 8 carbon atoms, or from 3to 6 carbon atoms. Examples of such cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

“Cycloalkylalkyl” as used herein, alone or in combination, means analkyl radical as defined above which is substituted by a cycloalkylradical as defined above. Examples of such cycloalkylalkyl radicalsinclude cyclopropylmethyl, cyclobutyl-methyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl,cyclopentylpropyl, cyclohexylbutyl and the like.

“Substituted” means that one or more of the hydrogen atoms bonded tocarbon atoms in the chain or ring have been replaced with othersubstituents. Suitable substituents include monovalent hydrocarbongroups including alkyl groups such as methyl groups and monovalentheterogeneous groups including alkoxy groups such as methoxy groups.“Unsubstituted” means that the carbon chain or ring contains no othersubstituents other than carbon and hydrogen.

“Hydrocarbon group” means a chain of 1 to 25 carbon atoms, 1 to 12carbon atoms, 1 to 10 carbon atoms, or 1 to 8 carbon atoms. Hydrocarbongroups may have a linear or branched chain structure. Suitably thehydrocarbon groups have one branch.

“Carbocyclic group” means a saturated or unsaturated hydrocarbon ring.Carbocyclic groups are not aromatic. Carbocyclic groups are monocyclicor polycyclic. Polycyclic carbocyclic groups can be fused, spiro, orbridged ring systems. Monocyclic carbocyclic groups contain 4 to 10carbon atoms, 4 to 7 carbon atoms, or 5 to 6 carbon atoms in the ring.Bicyclic carbocyclic groups contain 8 to 12 carbon atoms, or 9 to 10carbon atoms in the rings.

“Heteroatom” means an atom other than carbon e.g., in the ring of aheterocyclic group or the chain of a heterogeneous group. Heteroatomsmay be selected from the group consisting of sulfur, phosphorous,nitrogen, and oxygen atoms. Groups containing more than one heteroatommay contain different heteroatoms.

“Heterocyclic group” means a saturated or unsaturated ring structurecontaining carbon atoms and 1 or more heteroatoms in the ring.Heterocyclic groups are not aromatic. Heterocyclic groups are monocyclicor polycyclic. Polycyclic heteroaromatic groups can be fused, spiro, orbridged ring systems. Monocyclic heterocyclic groups contain 4 to 10member atoms (i.e., including both carbon atoms and at least 1heteroatom), 4 to 7, or 5 to 6 in the ring. Bicyclic heterocyclic groupscontain 8 to 18 member atoms, 9 or 10 in the rings.

“Isomer,” “isomeric form,” “stereochemically isomeric forms,” or“stereoisomeric forms”, as used herein, defines all possible isomeric aswell as conformational forms, made up of the same atoms bonded by thesame sequence of bonds but having different three-dimensional structureswhich are not interchangeable, which compounds or intermediates obtainedduring said process may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms which saidcompound may possess. Said mixture may contain all diastereoisomers,epimers, enantiomers and/or conformers of the basic molecular structureof said compound. More in particular, stereogenic centers may have theR- or S-configuration, diastereoisomers may have a syn- oranti-configuration, substituents on bivalent cyclic saturated radicalsmay have either the cis- or trans-configuration and alkenyl radicals mayhave the E- or Z-configuration. All stereochemically isomeric forms ofsaid compound both in pure form or in admixture with each other areintended to be embraced within the scope of the present disclosure.

EXAMPLES

The following examples are included to demonstrate various aspects ofthe present disclosure. It should be appreciated by those of skill inthe art that the techniques disclosed in the examples that followrepresent techniques discovered by the inventors to function well in thepractice of the disclosure, and thus can be considered to constitutepreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific examples which are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the disclosure.

The compounds of the present disclosure may be prepared in a number ofways well known to one skilled in the art of organic synthesis. Morespecifically, the novel compounds of this disclosure may be preparedusing the reactions and techniques described herein. In the descriptionof the synthetic methods described below, it is to be understood thatall proposed reaction conditions, including choice of solvent, reactionatmosphere, reaction temperature, duration of the experiment and workupprocedures, are chosen to be the conditions standard for that reaction.It is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reactions proposed. Such restrictionsto the substituents, which are not compatible with the reactionconditions, will be apparent to one skilled in the art and alternatemethods must then be used. Unless otherwise stated, the startingmaterials for the examples contained herein are either commerciallyavailable or are readily prepared by standard methods from knownmaterials. The compounds of Formula (I) or (II) may be synthesizedthrough standard organic chemistry methodology and purification known tothose trained in the art of organic synthesis by using commerciallyavailable starting materials and reagents.

All reactions were performed under a positive pressure of dry argonunless otherwise indicated. Analytical thin layer chromatography (TLC)was performed on ANALTECH 0.15 mm silica gel 60-GF254 plates.Visualization was accomplished with exposure to UV light, exposure toIodine or by dipping in an ethanolic phosphomolybdic acid solutionfollowed by heating. Solvents for extraction were HPLC or ACS grade.Flash chromatography was performed with DYNAMIC ADSORBENTS silica gel60A (32-63μ, 230-400 mesh) with the indicated solvent system. NMRspectra were collected on a JEOL ECS-400 NMR spectrometer. ¹H NMRspectra were reported in ppm from tetramethylsilane (TMS) on the δscale. Data are reported as follows: chemical shift, multiplicity(s=singlet, d=doublet, t=triplet, q=quartet, quint=quintet, etc.;m=multiplet, complex multiplets used where overlapping multiplets arenot resolved, b=broadened, obs=obscured, ABq=AB quartet, “apparent” used(e.g. apparent t) when spin systems are distorted due to non-first ordereffects), coupling constants (Hz), and assignments or relativeintegration where appropriate. ¹³C NMR spectra were reported in ppm fromthe central deuterated solvent peak (multiplicities indicated whendetermined). Grouped shifts are provided where an ambiguity has not beenresolved. LCMS were run on a WATERS ALLIANCE—SQ 3100 system using aThermo Scientific HYPERSIL GOLD (C18, 4.6×150 mm, 5-Micron) column andacetonitrile-water (0.05% trifluoroacetic acid) gradients.

The following abbreviations are used herein: ACN=acetonitrile;CH₂Cl₂=dichloromethane; DCC=N,N-Dicyclohexylcarbodiimide;DIAD=diisopropyl azodicarboxylate; DMF=dimethylformamide;DMSO=dimethylsulfoxide; EDC=N′-ethylcarbodiimide hydrochloride;HCI=hydrochloric acid; HOBt.H₂O=1-hydroxybenzotriazole hydrate;IRMS=high resolution mass spectroscopy; Hz=hertz; LCMS=liquidchromatography mass spectroscopy; LiAlH₄=lithium aluminum hydride;MeOH=methanol; Na₂SO₄=sodium sulfate; TEA=triethylamine;TFA=trifluoroacetic acid; THE=tetrahydrofuran; Trt-Cl=trityl chloride;Pd/C=palladium on carbon; PPh₃=triphenylphosphine; ppm=parts permillion; and SiO₂=silicon dioxide.

Example 1: Synthesis of 3,4,5-Trisubstituted-1,2,4-Triazoles Synthesisof (E)-methyl 3-(1H-imidazol-4-yl)acrylate hydrochloride (2)

Urocanic acid 1 (25.0 g, 181 mmol) was suspended in MeOH (700 mL) andtreated with 4N HCl/Dioxane (118 mL). The resulting mixture was stirredovernight at room temperature. Concentration of the reaction afforded34.0 g (100% yield) of compound 2 as a white solid: ¹H NMR (400 MHz,DMSO-d₆) δ 9.17 (s, 1H), 8.01 (s, 1H), 7.54 (d, J=16.0 Hz, 1H), 6.81 (dJ=16.0 Hz, 1H), 3.69 (s, 3H). LCMS (5-95% acetonitrile in 0.05% TFA over10 minutes) retention time=4.77 minutes, ESI m/z=153, [M+H]+.

Synthesis of methyl 3-(1H-imidazol-4-yl)propanoate hydrochloride (3)

(E)-Methyl 3-(1H-imidazol-4-yl)acrylate hydrochloride (2) (29.4 g, 156mmol) was dissolved in MeOH (700 mL) in an argon filled glovebox. Tothis solution was added 5% Pd/C (4 g). The mixture was brought out ofthe glovebox and fitted with a balloon of H₂ gas. The mixture wasstirred for 48 hours at room temperature. During this time the balloonwas periodically refilled with H₂. When the reaction was complete (asjudged by LCMS analysis), the mixture was purged with argon and filteredthrough a pad of CELITE. Concentration of the filtrate afforded 28.9 g(98% yield) of compound 3 as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ8.94 (s, 1H), 7.37 (s, 1H), 3.57 (s, 3H), 2.87 (t, J=7.30 Hz, 2H), 2.71(t, J=7.30 Hz, 2H). ¹³C (100 MHz, DMSO-d₆) δ 172.58 (s), 133.92 (d),132.55 (s), 116.13 (d), 52.08 (q), 32.42 (t), 20.01 (t). LCMS (5-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=3.67 minutes,ESI m/z=155, [M+H]⁺.

Synthesis of methyl 3-(1-trityl-1H-imidazol-4-yl)propanoate (4)

Methyl 3-(1H-imidazol-4-yl)propanoate hydrochloride (3) (15.0 g, 78.7mmol) was dissolved in CH₂Cl₂ (400 mL) and treated with trimethylamine(23.0 mL, 165 mmol). To this stirred mixture was added a solution oftriphenylmethyl chloride (21.9 g, 78.7 mmol) in CH₂Cl₂ (200 mL)dropwise. After stirring for 16 hours at room temperature, the mixturewas transferred to a separatory funnel and washed with water (2×250 mL).The organic layer was dried (Na₂SO₄), filtered and concentrated. Theresidue was recrystallized from methanol-water to afford 24.1 g (77%yield) of compound 4 as a white solid: ¹H NMR (400 MHz, CHCl₃) δ7.30-7.34 (complex multiplets, 10H), 7.08-7.13 (m, 5H), 6.53 (s, 1H),3.60 (s, 3H), 2.86 (t, J=7.80 Hz, 2H), 2.64 (t, J=7.30 Hz, 2H). ¹³C NMR(100 MHz, CHCl₃) δ 173.70 (s), 142.51 (s), 139.97 (d), 138.46 (s),129.86 (d), 128.08 (d), 118.18 (d), 75.61 (s), 51.61 (q), 33.97 (t),23.93 (t). LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=3.78 minutes, ESI m/z=397, [M+H]⁺.

Synthesis of 3-(1-trityl-1H-imidazol-4-yl)propan-1-01 (5)

To a solution of methyl 3-(1-trityl-1H-imidazol-4-Apropanoate (4) (56.6g, 143 mmol) in THF (300 mL) cooled in an ice-salt bath, was addedLiAlH₄ (100 mL of a 2.4 M solution in THF, 240 mmol) drop-wise at a ratewhich maintained the temperature under 5° C. The reaction was stirred at0-5° C. for 10 minutes post-addition, allowed to warm to roomtemperature (˜1 hour) and heated to reflux for 1 hour. The mixture wasthen cooled to 0-5° C. and carefully quenched by the drop-wise additionof 0.5 N NaOH (20 mL). The mixture was then filtered and the solidswashed with CH₂Cl₂. The filtrate was concentrated to afford 41.2 g (78%yield) of compound 5 as a white solid: ¹H NMR (400 MHz, CHCl₃) δ 7.37(d, J=1.40 Hz, 1H), 7.31-7.34 (m, 10H), 7.09-7.14 (m, 5H), 6.54 (s, 1H),3.72 (t, J=6.00 Hz, 2H), 2.68 (t, J=6.90 Hz, 2H), 1.85 (quint., J=6.8Hz, 2H). ¹³C NMR (100 MHz, CHCl₃) δ 142.92 (s), 141.57 (d), 138.10 (s),129.72 (d), 128.69 (d), 128.46 (d), 117.85 (d), 74.84 (s), 60.79 (t),32.75 (t), 24.96 (t). LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=2.97 minutes, ESI m/z=369, [M+H]⁺.

Synthesis of 2-(3-(1-trityl-1H-imidazol-4-yl)propypisoindoline-1,3-dione(6)

To a solution of 3-(1-trityl-1H-imidazol-4-Apropan-1-ol (5) (11.0 g,29.9 mmol) in THF (200 mL) was added phthalimide (6.51 g, 44.2 mmol) andtriphenylphosphine (11.7 g, 44.6 mmol). The resulting mixture was cooledto 0-5° C. and treated with a solution of diisopropylazodicarboxylate(12.6 mL, 63.8 mmol) in THF (50 mL) dropwise over 2.5 hours. Thereaction was allowed to stir for 16 hours and warm to room temperature.The solid product was filtered and washed with cold THF (100 mL). Thesolid was triturated with hot ACN (˜500 mL) and filtered to afford 13.1g (88% yield) of compound 6 as a fine white powder: ¹H NMR (400 MHz,CHCl₃) δ 7.80 (ddd, J=8.20, 5.00, 1.40 Hz, 2H), 7.68 (ddd, J=8.20, 5.00,1.40 Hz, 2H), 7.36 (d, J=0.90 Hz, 1H), 7.29-7.33 (m, 10H), 7.09-7.14 (m,5H), 6.57 (s, 1H), 3.71 (t, J=6.90 Hz, 2HH), 2.60 (t, J=7.40 Hz, 2H),1.99 (quint., J=7.30 Hz, 2H). LCMS (50-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=5.35 minutes, ESI m/z=498, [M+H]⁺.

Synthesis of 3-(1-Trityl-1H-imidazol-4-yl)propan-1-amine (7)

A suspension of2-(3-(1-trityl-1H-imidazol-4yl)propyl)isoindoline-1,3-dione (6) (10.2 g,20.6 mmol) in ethanol (500 mL) was treated with hydrazine hydrate (8.00mL of 98%, 162 mmol) and heated to reflux for 5 hours. The reactionmixture was allowed to cool and stir over night. The mixture wasfiltered to remove the precipitated phthalhydrazide and triturated withCH₂Cl₂ (400 mL) for 5 hours. Filtration to remove the remainingphthalhydrazide and concentration of the filtrate afforded 7.66 g (100%yield) of pure amine 7 as an off white foam: ¹H NMR (400 MHz, CHCl₃) δ7.29-7.32 (m, 10H), 7.09-7.13 (m, 6H), 6.51 (s, 1H), 2.73 (t, J=6.90 Hz,2H), 2.57 (t, J=7.80 Hz, 2H), 2.41 (bs, 2H), 1.77 (quint., J=6.90 Hz,2H). ¹³C NMR (100 MHz, CHCl₃) δ 142.60 (s), 141.23 (d), 138.37 (s),129.86 (d), 128.08 (d), 117.92 (s), 75.17 (s), 41.67 (t), 32.77 (t),25.88 (t). LCMS (25-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=5.75 minutes, ESI m/z=368, [M+H]⁺.

Synthesis of 3-(1H-indol-3-3/1)-N-(3-(1-trityl-1H-imidazol-4-Apropyl)propanamide (9)

To a solution of 3-(1H-indol-3-yl)propanoic acid (8) (5.66 g, 29.9 mmol)in DMF (80 mL) was added EDC.HCl (8.60 g, 44.9 mmol) and HOBtH₂O (5.70g, 37.2 mmol). The resulting mixture was stirred at room temperature for45 minutes. A solution of the amine 7 (11.0 g, 29.9 mmol) in DMF (80 mL)and TEA (6.00 mL, 43.0 mmol) was added and the reaction was stirred for16 hours at room temperature. The mixture was poured into water (500 mL)in a large beaker and stirred for 30 minutes at room temperature. Thesolid was collected by filtration. Recrystallization from ACN afforded11.8 g (73% yield) of pure amide 9: ¹H NMR (400 MHz, DMSO-d₆) δ 10.70(bs, 1H), 7.78 (t, J=5.50 Hz, 1H), 7.46 (d, J=7.80 Hz, 1H), 7.31-7.38(complex multiplets, 9H), 7.25 (d, J=7.80 Hz, 1H), 7.20 (s, 1H),7.02-7.05 (m, 7H), 6.99 (t, J=8.20 Hz, 1H), 6.56 (s, 1H), 2.99 (q, J=5.9Hz, 2H), 2.85 (t, J=7.70 Hz, 2H), 2.34-2.38 (m, 4H), 1.58 (quint.,J=7.40 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) A 172.20 (s), 142.90 (s),141.17 (d), 138.14 (s), 136.71 (s), 129.72 (d), 128.71 (d), 128.47 (d),127.54 (s), 122.57 (d), 121.36 (d), 118.87 (d), 118.60 (d), 118.11 (d),114.3 (s), 111.78 (d), 74.85 (s), 38.58 (t), 36.89 (t), 29.37 (t), 25.79(t), 21.61 (t). LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=4.87 minutes, ESI m/z=539, [M+H]⁺.

Synthesis of 3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide (10)

A mixture of3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanamide (9)(6.46 g, 12.0 mmol) and Lawesson's reagent (3.15 g, 7.80 mmol) in THF(100 mL) was heated to 65° C. for 4 hours. The reaction was cooled andconcentrated. The residue was purified by flash column chromatography(SiO₂, 10/1 CH₂CI₂/MeOH) to afford 3.34 g (50% yield) of thioamide 10 asa tan foam: ¹H NMR (400 MHz, DMSO-d₆) contains a small amount ofinseparable imidothioic phosphonate intermediate adduct of the startingamide with Lawesson's reagent (ESI m/z=741, [M+H]⁺); desired thioamidecomponent: δ 10.73 (bs, 1H), 9.96 (t, J=5.10 Hz, 1H), 7.50 (d, J=7.80Hz, 1H), 7.34-7.40 (complex multiplets, 10H), 7.26 (d, J=7.80 Hz, 1H),7.05-7.09 (m, 6H), 6.99 (t, J=7.70 Hz, 1H), 6.90 (t, J=7.70 Hz, 1H),3.43 (apparent q, J=6.00 Hz, 2H), 3.02 (apparent t, J=7.80 Hz, 2H), 2.82(apparent t, J=7.75 Hz, 2H), 2.42 (t, J=6.80 Hz, 2H), 1.76 (quint,J=7.30 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 203.79 (s), 142.45 (s),137.93 (s), 136.70 (d), 129.74 (d), 128.83 (d), 128.63 (d), 127.54 (s),122.75 (d), 121.41 (d), 118.91 (d), 118.64 (d), 113.86 (s), 111.83 (s),75.53 (s), 46.51 (t), 45.22 (t), 27.15 (t), 25.67 (t), 25.02 (t). LCMS(50-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=5.85minutes, ESI m/z=555, [M+H]⁺

Synthesis of 3-(1-methyl-1H-indol-3-yl)propanoic acid (12)

To a solution of 3-(1H-indol-3-yl)propanoic acid (8) (3.00 g, 15.9 mmol)in acetone (70 mL) was added methyl iodide (5.00 mL, 80.3 mmol) and KOH(5.30 g, 94.4 mmol) at 0° C. The reaction was stirred for 4 hours andthe solvent was evaporated. The residue was dissolved in H₂O (100 mL)and treated with KOH (4.50 g, 80.2 mmol). The resulting mixture wasrefluxed for 2 hours, cooled to 0° C., and acidified to pH ˜1 with 6NHCI. The product was isolated by filtration and washed with heptane(˜100 mL) to afford 3.20 g (99% yield) of compound 12 as a yellow solid:¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (bs, 1H), 7.48 (d, J=7.80 Hz, 1H),7.33 (d, J=8.20 Hz, 1H), 7.09 (t, J=8.20 Hz, 1H), 7.05 (s, 1H), 6.96 (t,J=7.80 Hz, 1H), 3.68 (s, 3H), 2.87 (t, J=7.80 Hz, 2H), 2.53 (t, J=7.40Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 174.68, 137.13, 127.75, 127.23,121.59, 118.85, 113.26, 110.06, 35.11, 32.75, 20.66. LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=3.50 minutes,ESI m/z=204, [M+H]⁺.

Synthesis of3-(1-methyl-1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)-propanamide13)

To a solution of 3-(1-methyl-1H-indol-3-yl)propanoic acid (12) (503 mg,2.47 mmol) in DMF (30 mL) was added EDC.HCl (592 mg, 3.09 mmol) andHOBt.H₂O (476 mg, 3.09 mmol). The resulting mixture was stirred at roomtemperature for 45 minutes. A solution of the amine 7 (908 mg, 2.47mmol) in DMF (20 mL) and TEA (700 μL, 5.00 mmol) was added and thereaction was stirred for 16 hours at room temperature. The DMF wasevaporated and the residue was partitioned with CH₂Cl₂ (150 mL) andwater (150 mL). The layers were separated and the organic solution waswashed with saturated NaHCO₃ (150 mL) and brine (150 mL). The organiclayer was then dried (Na₂SO₄), filtered and concentrated to afford 650mg (48% yield) of compound 13 as a tan solid: ¹H NMR (400 MHz, CDCl₃) δ7.54 (d, J=7.80 Hz, 1H), 7.30-7.34 (complex multiplets, 10H), 7.28 (d,J=4.50 Hz, 1H), 7.22-7.25 (m, 1H), 7.17 (dt, J=6.80, 0.90 Hz, 1H),7.08-7.11 (m, 5H), 7.02 (dt, J=6.90, 0.90 Hz, 1H), 6.83 (s, 1H), 6.47(s, 1H), 6.25 (bt, J=4.60 Hz, 1H), 3.66 (t, 3H), 3.22 (apparent q,J˜6.00 Hz, 2H), 3.07 (t, J=7.30 Hz, 2H), 2.51 (t, J=7.80 Hz, 2H), 2.44(t, J=7.30 Hz, 2H), 1.72 (quint, J=6.80 Hz, 2H). ¹³C NMR (100 MHz,CDCl₃) δ 172.85, 142.40, 140.61, 138.17, 137.05, 129.81, 128.15, 128.01,126.57, 121.57, 118.93, 118.76, 118.25, 113.72, 109.24, 75.36, 39.11,37.75, 32.63, 28.55, 25.46, 21.45. LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=6.40 minutes, ESI m/z=553, [M+H]⁺.

Synthesis of3-(1-methyl-1H-indol-3-0-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propane-thioamide14)

A solution of3-(1-methyl-1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)-propanamide(13) (azeotropically dried by coevaporation with toluene, 620 mg, 1.12mmol) and Lawesson's reagent (295 mg, 0.73 mmol) in THF (30 mL) washeated to 65° C. for 4 hours. The resulting mixture was allowed to coolto room temperature and concentrated. Purification by flash columnchromatography (SiO₂, 40:1 to 20:1 CH₂Cl₂/MeOH) afforded 470 mg (78%yield) of compound 14 as a yellow foam: ¹H NMR (400 MHz, DMSO-d₆) δ 9.92(bt, J˜5.00 Hz, 1H), 7.51 (d, J=8.20 Hz, 1H), 7.30 7.39 (complexmultiplets, 10H), 7.27 (t, J=8.20 Hz, 1H), 7.02-7.06 (m, 7H), 6.93 (t,J=7.30 Hz, 1H), 6.60 (s, 1H), 3.62 (s, 3H), 3.42 (apparent q, J˜6.20 Hz,2H), 3.01 (t, J=7.40 Hz, 2H), 2.79 (t, J=7.30 Hz, 2H), 2.36 (t, J=7.30Hz, 2H), 1.73 (quint, J=7.30 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ203.59, 142.71, 140.29, 138.09, 137.08, 129.73, 128.77, 128.53, 127.85,127.25, 121.53, 119.16, 118.73, 118.39, 113.15, 109.98, 75.13, 46.56,45.33, 40.69, 32.70, 27.27, 25.45. LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=6.40 minutes, ESI m/z=569, [M+H]⁺.

Synthesis of tert-butyl (2-(3-(1H-indol-3-yl)propanamido)ethyl)carbamate (16)

To a solution of 3-(1H-indol-3-yl)propanoic acid (8) (3.00 g, 15.9 mmol)in DMF (80 mL) was added EDC.HCl (4.56 g, 23.8 mmol) and HOBt.H₂O (3.64g, 23.8 mmol). The resulting mixture was stirred at room temperature for30 minutes. A solution of the amine 15 (3.00 g, 18.7 mmol) in DMF (20mL) and TEA (3.50 mL, 25.1 mmol) was added and the reaction was stirredfor 16 hours at room temperature. The DMF was evaporated and the residuewas partitioned with EtOAc (150 mL) and water (150 mL). The layers wereseparated and the organic solution was washed with 1N NaHSO₄ (150 mL),saturated NaHCO₃ (150 mL) and brine (150 mL). The organic layer was thendried (Na₂SO₄), filtered and concentrated to afford 5.12 g (97% yield)of compound 16 as a white foam: LCMS (50-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=2.87 minutes, ESI m/z=332, [M+H]⁺.

Synthesis of tert-butyl (2-(3-(1H-indol-3-yl)Drobanethioamido)ethyl)carbamate (17)

A solution of tert-butyl(2-(3-(1H-indol-3-yl)propanamido)ethyl)carbamate (16) (azeotropicallydried by coevaporation with toluene, 4.74 g, 14.3 mmol) and Lawesson'sreagent (3.18 g, 7.86 mmol) in THE (50 mL) was heated to 65° C. for 4hours. The resulting mixture was allowed to cool to room temperature andconcentrated. Purification by flash column chromatography (SiO₂, 3:1hexanes/EtOAc to 1:1) afforded 3.86 g (78% yield) of compound 17 as anorange foam: LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=5.45 minutes, ESI m/z=348, [M+H]⁺.

Synthesis of tert-butyl (4-(3-(1H-indol-3-yl)propanamido)butyl)carbamate (19)

To a solution of 3-(1H-indol-3-yl)propanoic acid (8) (1.00 g, 5.29 mmol)in DMF (40 mL) was added EDC.HCl (1.52 g, 7.93 mmol) and HOBt.H₂O (1.21g, 7.93 mmol). The resulting mixture was stirred at room temperature for30 minutes. A solution of the amine 18 (1.10 g, 5.82 mmol) in DMF (10mL) and TEA (1.50 mL, 10.8 mmol) was added and the reaction was stirredfor 16 hours at room temperature. The DMF was evaporated and the residuewas partitioned with EtOAc (150 mL) and water (150 mL). The layers wereseparated and the organic solution was washed with 1N NaHSO₄ (150 mL),saturated NaHCO₃ (150 mL) and brine (150 mL). The organic layer was thendried (Na₂SO₄), filtered and concentrated to afford 1.90 g (100% yield)of compound 19 as a white foam: ¹H NMR (400 MHz, CDCl₃) δ 8.59 (bs, 1H0,7.59 (d, J=7.80 Hz, 1H), 7.36 (d, J=8.20 Hz, 1H), 7.17 (t, J=7.30 Hz,1H), 7.09 (t, J=7.20 Hz, 1H), 6.99 (d, J=1.40 Hz, 1H), 5.47 (bs, 1H),4.59 (bs, 1H), 3.09-3.13 (m, 4H), 2.97-3.02 (m, 2H), 2.54 (t, J=6.90 Hz,2H), 1.45 9s, 9H), 1.17-1.31 (complex multiplets, 4H). ¹³C NMR (100 MHz,CDCl₃) δ 173.05, 156.39, 136.51, 127.09, 122.33, 121.98, 118.71, 114.53,111.47, 79.51, 40.30, 39.12, 37.60, 28.57, 27.69, 26.79, 21.68. LCMS(40-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=3.83minutes, ESI m/z=360, [M+H]⁺.

Synthesis of tert-butyl (4-(3-(1H-indol-3-yl)propanethioamido)butyl)carbamate (20)

A solution of tert-butyl(4-(3-(1H-indol-3-yl)propanamido)butyl)carbamate (19) (azeotropicallydried by coevaporation with toluene, 654 mg, 1.82 mmol) and Lawesson'sreagent (404 mg, 1.00 mmol) in THF (50 mL) was heated to 65° C. for 1hour. The resulting mixture was allowed to cool to room temperature andconcentrated. Purification by flash column chromatography (SiO₂, 1:1hexanes/EtOAc) afforded 471 mg (69% yield) of compound 20 as a yellowfoam: ¹H NMR (400 MHz, CDCl₃) δ 8.58 (bs, 1H), 7.61 (d, J=7.80 Hz, 1H),7.39 (d, J=8.30 Hz, 1H), 7.32 (bs, 1H), 7.18 (dt, J=7.10, 0.90 Hz, 1H),7.10 (dt, J=7.80, 0.90 Hz, 1H), 7.01 (s, 1H), 4.56 (bs, 1H), 3.46(apparent q, J=5.95 Hz, 2H), 3.25 (t, J=6.90 Hz, 2H), 3.02 (t, J=6.90Hz, 2H), 2.95 (bt, J˜6.40 Hz, 1H), 1.46 (s, 9H), 1.27-1.34 (m, 2H),1.10-1.18 (m, 2H). LCMS (40-95% acetonitrile in 0.05% TFA over 10minutes) retention time=5.78 minutes, ESI m/z=376, [M+H]⁺.

Synthesis of tert-butyl (5-(3-(1H-indol-3-yl)propanamido)pentyl)carbamate (22)

To a solution of 3-(1H-indol-3-yl)propanoic acid (8) (1.00 g, 5.29 mmolin DMF (30 mL) was added EDC.HCl (1.52 g, 7.93 mmol) and HOBt.H₂O (1.21g, 7.93 mmol). The resulting mixture was stirred at room temperature for30 minutes. A solution of the amine 21 (1.18 g, 5.82 mmol) in DMF (10mL) and TEA (2.00 mL, 14.3 mmol) was added and the reaction was stirredfor 16 hours at room temperature. The DMF was evaporated and the residuewas partitioned with EtOAc (150 mL) and water (150 mL). The layers wereseparated and the organic solution was washed with 1N NaHSO₄ (150 mL),saturated NaHCO₃ (150 mL) and brine (150 mL). The organic layer was thendried (Na₂SO₄), filtered and concentrated to afford 1.99 g (100% yield)of compound 22 as a tan foam: ¹H NMR (400 MHz, CDCl₃) δ 9.06 (bs, 1H),7.58 (d, J=7.80 Hz, 1H), 7.38 (d, J=7.80 Hz, 1H), 7.17 (dt, J=6.90, 1.00Hz, 1H), 7.09 (dt, J=7.80, 0.90 Hz, 1H), 7.00 (d, J=2.30 Hz, 1H), 5.34(bs, 1H), 4.62 (bs, 1H), 3.07-3.13 (m, 4H), 3.02 (apparent q, J˜6.75 Hz,2H), 2.54 (t, J=7.30 Hz, 2H), 1.46 (s, 9H), 1.33 (quint, J=7.30 Hz, 2H),1.20-1.26 (m, 2H), 0.93-1.01 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 173.05,156.49, 136.67, 127.02, 122.42, 121.86, 119.17, 118.60, 114.21, 111.57,79.57, 40.50, 39.16, 37.59, 30.05, 29.15, 28.55, 23.70, 21.72. LCMS(40-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=4.12minutes, ESI m/z=374, [M+H]⁺.

Synthesis of tert-butyl (5-(3-(1H-indol-3-yl)propanethioamido)pentyl)carbamate (23)

A solution of tert-butyl (5-(3-(1H-indol-3-yl)propanamido)pentyl)carbamate (22) (azeotropically dried by coevaporation with toluene, 1.99g, 5.33 mmol) and Lawesson's reagent (1.19 g, 2.93 mmol) in THF (50 mL)was heated to 65° C. for 1 hour. The resulting mixture was allowed tocool to room temperature and concentrated. Purification by flash columnchromatography (SiO₂, 1:1 hexanes/EtOAc) afforded 1.20 g (58% yield) ofcompound 23 as a yellow foam: LCMS (40-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=6.17 minutes, ESI m/z=390, [M+H]⁺.

Synthesis of (R)-tert-butyl(3-(1H-indol-3-yl)-1-oxo-1-((3-(1-trityl-1H-imidazol-4-yl)propyl)-amino)propan-2-yl)carbamate(25)

To a solution of N-Boc-D-Tryptophan (597 mg, 1.96 mmol, purchased fromChem-Impex International, Cat. #01387) (24) in DMF (50 mL) was addedEDC.HCl (470 mg, 2.45 mmol) and HOBt.H₂O (375 mg, 2.45 mmol). Theresulting mixture was stirred at room temperature for 30 minutes. Asolution of the amine 7 (721 mg, 1.96 mmol) in DMF (30 mL) and TEA (400μL, 2.87 mmol) was added and the reaction was stirred for 16 hours atroom temperature. The DMF was evaporated and the residue was partitionedwith EtOAc (75 mL) and water (75 mL). The layers were separated and theorganic solution was washed with 1N NaHSO₄ (75 mL), saturated NaHCO₃ (75mL) and brine (75 mL). The organic layer was then dried (Na₂SO₄),filtered and concentrated to afford 1.02 g (80% yield) of compound 25 asa tan solid: ¹H NMR (400 MHz DMSO-d₆) δ 10.75 (bs, 1H), 7.84 (t, J=6.00Hz, 1H), 7.71 (d, J=8.30 Hz, 1H), 7.32-7.39 (complex m, 10H), 7.27-7.27(m, 2H), 7.20 (d, J=0.90 Hz, 1H), 7.03-7.06 (m, 3H), 6.97 (t, J=7.30 Hz,1H), 6.89 (t, J=6.80 Hz, 1H), 6.69 (d, J=8.20 Hz, 1H), 6.54 (s, 1H),4.08 (dt, J=8.70, 5.00 Hz, 1H), 2.95-3.02 (m, 3H), 2.80-2.86 (m, 1H),2.33 (t, J=7.30 Hz, 2H), 1.56 (quint, J=7.30 Hz, 2H). LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=5.88 minutes,ESI m/z=654, [M+H]⁺.

Synthesis of (R)-tert-butyl(3-(1H-indol-3-yl)-1-thioxo-1-((3-(1-trityl-1H-imidazol-4-yl)propyl)amino)propan-2-yl)carbamate(26)

A solution of (R)-tert-butyl(3-(1H-indol-3-yl)-1-oxo-1-((3-(1-trityl-1H-imidazol-4-yl)propyl)-amino)propan-2-yl)carbamate(25) (azeotropically dried by coevaporation with toluene, 450 mg, 0.69mmol) and Lawesson's reagent (240 mg, 0.59 mmol) in THF (40 mL) washeated to 65° C. for 4 hours. The resulting mixture was allowed to coolto room temperature and concentrated. Purification by flash columnchromatography (SiO₂, 1:1 hexanes/EtOAc) afforded 289 mg (58% yield) ofcompound 26 as an orange-brown foam: LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=6.81 minutes, ESI m/z=670, [M+H]⁺.

General Procedure 1A: Boc-Protected Hydrazides

A mixture of the carboxylic acid (1.00 mmol), EDC.HCl (1.25 equiv.),HOBt.H₂O (1.25 equiv.) in DMF (50 mL) was stirred at room temperaturefor 30 minutes. The resulting mixture was treated with tert-butylhydrazinecarboxylate (1.25 equiv.) and TEA (5 mL) and stirred for 16hours. The solvent was evaporated and the residue was partitionedbetween EtOAc (150 mL) and 1N Na₂SO₄ (150 mL). The layers were separatedand organic layer was washed with H₂O (150 mL), saturated NaHCO₃ (150mL) and brine (150 mL). The organic layer was dried (anhydrous Na₂SO₄),filtered, and concentrated.

Synthesis of tert-Butyl 2-(2-(4-chloroDhenynacetyl) hydrazinecarboxylate (28a)

Prepared according to the General Procedure 1A from2-(4-chlorophenyl)acetic acid (27a) (3.00 g, 17.6 mmol) and tert-butylhydrazinecarboxylate (2.91 g, 22.0 mmol) to afford 4.91 g (98% yield) ofcompound 28a as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (bs,1H), 8.75 (bs, 1H), 7.33 (d, J=8.70 Hz, 2H), 7.25 (d, J=8.70 Hz, 2H),3.30 (s, 2H), 1.34 (s, 9H). LCMS (50-95% acetonitrile in 0.05% TFA over10 minutes) retention time=3.65 minutes, ESI m/z=285, [M+H]⁺.

Synthesis of tert-Butyl 2-(2-(3-chloroDhenynacetyl) hydrazinecarboxylate (28b)

Prepared according to the General Procedure 1A from2-(3-chlorophenyl)acetic acid (27b) (3.17 g, 18.6 mmol) and tert-butylhydrazinecarboxylate (3.07 g, 23.3 mmol) to afford 5.25 g (99% yield) ofcompound 28b as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.81 (bs, 1H),7.24 (m, 2H), 7.17-7.19 (m, 1H), 6.64 (bs, 1H), 3.55 (s, 2H), 1.43 (s,9H). ¹³C NMR (100 MHz, CDCl₃) δ 169.71 (s), 155.60 (s) 135.75 (s),134.72 (s), 130.23 (d), 129.55 (d), 127.77 (d), 127.63 (d), 82.21 (s),40.84 (t), 28.20 (q). LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=3.73 minutes, ESI m/z=285, [M+H]⁺, m/z=569[2M+H]⁺.

Synthesis of tert-Butyl 2-(2-(2-chlorophenyl)acetyl) hydrazinecarboxylate (28c)

Prepared according to the General Procedure 1A from2-(2-chlorophenyl)acetic acid (27c) (3.01 g, 17.6 mmol) and tert-butylhydrazinecarboxylate (2.91 g, 22.1 mmol) to afford 2.30 g (46% yield) ofcompound 28c as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (bs,1H), 8.77 (bs, 1H), 7.36-7.39 (m, 2H), 7.22-7.27 (m, 2H), 3.53 (s, 2H),1.35 (s, 9H). ¹³C NMR (100 MHz, DMSO-d₆) δ 169.17 (s), 155.74 (s), 134(s), 132.31 (d), 129.49 (d), 129.05 (d), 127.53 (d), 127.45 (s), 79.60(s), 38.03 (t), 28.57 (q). LCMS (50-95% acetonitrile in 0.05% TFA over10 minutes) retention time=3.30 minutes, ESI m/z=285, [M+H]⁺, m/z=569[2M+H]⁺.

Synthesis of tert-Butyl 2-(2-(4-methoxyphenyl)acetyl) hydrazinecarboxylate (28d)

Prepared according to the General Procedure 1A from2-(4-methoxyphenyl)acetic acid (27d) (3.00 g, 18.0 mmol) and tert-butylhydrazinecarboxylate (2.98 g, 22.5 mmol) to afford 4.97 g (98% yield) ofcompound 28d as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (bs, 1H),8.70 (bs, 1H), 7.14 (d, J=8.70 Hz, 2H), 6.82 (d, J=8.70 Hz, 2H), 3.68(s, 3H), 3.29 (s, 2H), 1.35 (s, 9H). ¹³C NMR (100 MHz, DMSO-d₆) δ171.07, 158.89, 155.76, 130.51, 126.00, 114.34, 81.83, 55.03, 40.39,28.21. LCMS (40-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=3.88 minutes, ESI m/z=281, [M+H]⁺, m/z=561 [2M+H]⁺.

Synthesis of tert-Butyl 2-(2-(3-methoxyphenyl)acetyl) hydrazinecarboxylate (28e)

Prepared according to the General Procedure 1A from2-(3-methoxyphenyl)acetic acid (27e) (2.43 g, 14.6 mmol) and tert-butylhydrazine carboxylate (2.41 g, 18.3 mmol) to afford 4.16 g (100% yield)of compound 28e as white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.40 (bs, 1H),7.25 (t, J=8.3 Hz, 1H), 6.81-6.87 (m, 3H), 6.51 (bs, 1H), 3.79 (s, 3H),3.58 (s, 2H), 1.43 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 170.24 (s),160.06 (s), 155.39 (s), 135.10 (s), 130.17 (d), 121.74 (d), 115.00 (d),113.28 (d), 82.00 (s), 55.33 (q), 41.71 (t), 28.19 (q). LCMS (40-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=4.13 minutes,ESI m/z=281, [M+H]⁺, m/z=561 [2M+H]⁺.

Synthesis of tert-Butyl 2-(2-(2-methoxyphenyl)acetyl)hydrazinecarboxylate (28f)

Prepared according to the General Procedure 1A from2-(2-methoxyphenyl)acetic acid (27f) (3.00 g, 18.0 mmol) and tert-butylhydrazinecarboxylate (2.98 g, 22.5 mmol) to afford 4.62 g (91% yield) ofcompound 28f as white solid: ¹H NMR (400 MHz, CDCl₃) rotational isomersobserved, δ 7.52 (bd, J 2.80 Hz, 1H), 7.24-7.29 (m, 2H), 6.93 (dt,J=7.70, 1.30 Hz, 1H), 6.90 (d, J=8.20 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃)rotational isomers observed, δ 170.53, 157.09, 155.30, 131.35, 129.14,122.50, 121.27, 110.86, 81.74, 55.69, 36.74, 28.16. LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=3.07 minutes,ESI m/z=281, [M+H]⁺, m/z=561 [2M+H]⁺.

Synthesis of tert-Butyl 2-(2-(3-fluorophenyl)acetyl)hydrazinecarboxylate (28g)

Prepared according to the General Procedure 1A from2-(3-fluorophenyl)acetic acid (27 g) (3.07 g, 19.9 mmol) and tert-butylhydrazinecarboxylate (3.29 g, 24.9 mmol) to afford 5.14 g (96% yield) ofcompound 28g as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.81 (bs,1H), 8.77 (bs, 1H), 7.31 (apparent q, JH,F˜6.90, JH,H−6.90 Hz, 1H),7.01-7.08 (m, 3H), 3.41 (s, 2H), 1.35 (s, 9H). LCMS (50-95% acetonitrilein 0.05% TFA over 10 minutes) retention time=2.98 minutes, ESI m/z=269,[M+H]⁺, m/z=537 [2M+H]⁺.

Synthesis of tert-Butyl 2-(2-(3-bromophenyl)acetyl)hydrazine carboxylate(28h)

Prepared according to the General Procedure 1A from2-(3-bromophenyl)acetic acid (27h) (5.00 g, 23.2 mmol) and tert-butylhydrazinecarboxylate (3.84 g, 29.0 mmol) to afford 7.14 g (97% yield) ofcompound 28h as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.71 (bs, 1H),7.45 (bs, 1H), 7.40 (d, J=6.00 Hz, 1H), 7.17-7.23 (m, 2H), 6.60 (bs,1H), 3.55 (s, 2H), 1.44 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 169.68,155.56, 136.00, 132.43, 130.73, 130.54, 128.10, 122.95, 82.23, 40.83,28.21. LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=3.97 minutes, ESI m/z=329, [M+H]⁺, m/z=657 [2M+H]⁺.

Synthesis of tert-Butyl 2-(2-(3-(trifluoromethyl)phenylacetyl) hydrazinecarboxylate (28i)

Prepared according to the General Procedure 1A from2-(3-bromophenyl)acetic acid (27i) (3.00 g, 14.7 mmol) and tert-butylhydrazinecarboxylate (1.94 g, 14.7 mmol) to afford 4.52 g (97% yield) ofcompound 28i as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.01 (bs, 1H),7.49-7.54 (m, 3H), 7.41-7.45 (m, 1H), 3.61 (s, 2H), 1.43 (s, 9H). ¹³CNMR (100 MHz, CDCl₃) δ 169.64, 155.65, 134.81, 132.82, 131.18 (q,J_(C,F)=32.6 Hz), 129.39, 126.15 (q, J_(C,F)=3.80 Hz), 124.38 (q,J_(C,F)=3.90 Hz), 124.00 (q, J_(C,F)=272.2 Hz), 82.30, 40.78, 28.16.LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=4.43 minutes, ESI m/z=319, [M+H]⁺, m/z=637 [2M+H]⁺.

Synthesis of tert-Butyl 2-(2-(3,5-difluorophenynacetyl)hydrazinecarboxylate (28j)

Prepared according to the General Procedure 1A from2-(3,5-difluorophenyl)acetic acid (27j) (3.00 g, 17.4 mmol) andtert-butyl hydrazinecarboxylate (2.88 g, 21.8 mmol) to afford 3.05 g(61% yield) of compound 28j as a white solid: LCMS (50-95% acetonitrilein 0.05% TFA over 10 minutes) retention time=3.45 minutes, ESI m/z=287,[M+H]⁺, m/z=573 [2M+H]⁺.

Synthesis of tert-Butyl 2-(2-(3,5-difluorophenypacetyphydrazinecarboxylate (28k)

Prepared according to the General Procedure 1A from2-(3,5-dichlorophenyl)acetic acid (27k) (5.06 g, 24.7 mmol) andtert-butyl hydrazinecarboxylate (3.26 g, 24.7 mmol) to afford 6.81 g(86% yield) of compound 28k as a white solid: LCMS (50-95% acetonitrilein 0.05% TFA over 10 minutes) retention time=4.90 minutes, ESI m/z=319,[M+H]⁺; m/z=639, [2M+H]⁺.

Synthesis of tert-Butyl 2-(2-(3,4-dichlorophenylacetyl)hydrazinecarboxylate (28l)

Prepared according to the General Procedure 1A from2-(3,4-dichlorophenyl)acetic acid (27l) (2.43 g, 11.9 mmol) andtert-butyl hydrazinecarboxylate (1.97 g, 14.9 mmol) to afford 3.61 g(95% yield) of compound 28l as a white solid: ¹H NMR (400 MHz, CDCl₃) δ7.95 (bs, 1H), 7.39 (d, J=2.30 Hz, 1H), 7.38 (d, J=8.30 Hz, 1H), 7.14(dd, J=8.30, 2.30 Hz, 1H), 6.67 (bs, 1H), 3.51 (s, 2H), 1.44 (s, 9H).LCMS (40-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=2.10 minutes, ESI m/z=319, [M+H]⁺.

Synthesis of tert-Butyl 2-(2-(1-1,11-biphenyl-4-ynacetyl)hydrazinecarboxylate (AH.2.182)

Prepared according to the General Procedure 1A from2-([1,1′-biphenyl]-4-yl)acetic acid (27m) (3.00 g, 14.1 mmol) andtert-butyl hydrazinecarboxylate (3.39 g, 17.7 mmol) to afford 3.96 g(86% yield) of compound 28m as a white solid: ¹H NMR (400 MHz, DMSO-d₆)δ 9.80 (bs, 1H), 8.72 (bs, 1H), 7.55-7.62 (m, 4H), 7.41 (t, J=7.30 Hz,2H), 7.31-7.34 (m, 3H), 3.42 (s, 2H), 1.35 (s, 9H). ¹³C NMR (100 MHz,DMSO-d₆) δ 170.16, 155.79, 140.49, 138.95, 135.44, 130.16, 129.44,127.83, 127.08, 127.05, 79.62, 28.57. LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=5.23 minutes, ESI m/z=327, [M+H]⁺,653 [2M+H]+.

General Procedure 1B: Synthesis of Hydrazide Free Bases

To the Boc-hydrazide (1.00 mmol) in CH₂Cl₂ was added 4N HCl/Dioxane (10mL) and the reaction was stirred at room temperature. After 1.5 hours awhite precipitate was formed. The precipitated HCI salt was filtered andwashed with CH₂Cl₂ and dried under high vacuum. The salt (1.00 mmol) wassuspended in CH₂Cl₂ (75 mL) or dissolved in methanol (or methanol/water)and treated with TEA (6 mL). The resulting mixture was stirred at roomtemperature for 30 minutes, transferred to a separatory funnel andpartitioned with additional CH₂Cl₂ (75 mL) and water (150 mL).

The layers were separated and the organic solution was dried (anhydrousNa₂SO₄), filtered, and concentrated. This compound was used in the nextstep without further purification.

Synthesis of 2-(4-Chlorophenyl)acetic hydrazide (29a)

Prepared according to the General Procedure 1B from tert-Butyl2-(2-(4-chlorophenyl)acetyl)hydrazinecarboxylate (28a) (4.90 g, 17.2mmol) to afford 3.18 g (84% yield) of the intermediate HCI salt as awhite solid. The HCI salt was then converted to 860 mg (32% yield) offreebase 29a (27% for two steps), isolated as a white solid: LCMS(50-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=2.08minutes, ESI m/z=185, [M+H]⁺.

Synthesis of 2-(3-Chlorophenyl)acetic hydrazide (29b)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3-chlorophenyl)acetyl)hydrazinecarboxylate (28b) (5.00 g, 17.6mmol) to afford 3.02 g (78% yield) of the intermediate HCI salt as awhite solid. The HCI salt was then converted to 1.73 g (69% yield) offreebase 29b (54% for two steps), isolated as a white solid: ¹H NMR (400MHz, DMSO-d₆) δ 9.20 (bs, 1H), 7.23 7.30 (complex m, 3H), 1.15-7.18(complex m, 1H), 4.20 (bs, 2H), 3.32 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ171.00 (s), 135.92 (s), 134.83 (s), 130.30 (d), 129.52 (d), 127.82 (d),127.60 (d), 41.4 (t). LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=1.95 minutes, ESI m/z=185, [M+H]⁺; m/z=369,[2M+H]⁺; m/z=391, [2M+Na].

Synthesis of 2-(2-Chlorophenyl)acetic hydrazide (29c)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(2-chlorophenyl)acetyl)hydrazinecarboxylate (28c) (2.10 g, 7.37mmol) to afford 1.63 g (100% yield) of the intermediate HCI salt as awhite solid. The HCI salt (1.23 g, 5.56 mmol) was then converted to 830mg (81° A yield) of freebase 29c (81° A for two steps), isolated as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.17 (bs, 1H), 7.31-7.38(complex m, 2H), 7.20-7.26 (complex m, 2H), 4.20 (bs, 2H), 3.47 (s, 2H).¹³C NMR (100 MHz, DMSO-d₆) δ 168.95 (s), 134.54 (s), 133.94 (s), 132.32(d), 129.50 (d), 128.90 (d), 127.51 (d), 38.34 (t). LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=2.08 minutes,ESI m/z=185, [M+H]⁺; m/z=369, [2M+H]+; m/z=391, [2M+Na]⁺.

Synthesis of 2-(4-Methoxyphenyl)acetic hydrazide (29d)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(4-methoxyphenyl)acetyl)hydrazinecarboxylate (28d) (4.67 g, 16.7mmol) to afford 2.78 g (77% yield) of the intermediate HCI salt as awhite solid. The HCI salt (2.68 g, 12.4 mmol) was then converted to 1.18g (53% yield) of freebase 29d (41% for two steps), isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (bs, 2H), 7.12 (d, J=6.40 Hz,2H), 6.81 (d, J=6.90 Hz, 2H), 4.15 (bs, 2H), 3.67 (s, 3H), 3.22 (s, 2H).

Synthesis of 2-(3-Methoxyphenyl)acetic hydrazide (29e)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3-methoxyphenyl)acetyl)hydrazinecarboxylate (28e) (4.09 g, 14.6mmol) to afford 3.10 g (98% yield) of the intermediate HCI salt as awhite solid. The HCI salt (2.50 g, 11.5 mmol) was then converted to 1.10g (53% yield) of freebase 29e (52% for two steps), isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (bs, 1H), 7.15 (t, J=7.8 Hz,1H), 6.79 (s, 1H), 6.74-6.77 (complex m, 2H), 4.17 (bs, 2H), 3.68 (s,3H), 3.26 (s, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 169.93 (s), 159.63 (s),138.23 (s), 129.69 (d), 121.71 (d), 115.20 (d), 112.27 (d), 55.45 (q),41.03 (t). LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=1.85 minutes, ESI m/z=181, [M+H]⁺; m/z=361, [2M+H]+.

Synthesis of 2-(2-Methoxyphenyl)acetic hydrazide (29f)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(2-methoxyphenyl)acetyl)hydrazinecarboxylate (28f) (4.61 g, 16.4mmol) to afford 3.08 g (86% yield) of the intermediate HCI salt as awhite solid. The HCI salt (3.08 g, 14.2 mmol) was then converted to 1.88g (73% yield) of freebase 29f (63% for two steps), isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (bs, 1H), 7.16 (dt, J=7.80, 1.90Hz, 1H), 7.11 (d, J=7.30 Hz, 1H), 6.90 (d, J=7.80 Hz, 1H), 6.82 (t,J=7.30 Hz, 1H), 4.15 (bs, 1H), 3.70 (s, 3H), 3.28 (s, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 170.13 (s), 157.59 (s), 130.98 (d), 128.33 (d), 124.73(s), 120.57 (d), 111.10 (d), 55.86 (q), 35.02 (t). LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=1.85 minutes,ESI m/z=181, [M+H]⁺; m/z=361, [2M+H]⁺.

Synthesis of 2-(3-Fluorophenyl)acetic hydrazide (29 g)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3-fluorophenyl)acetyl)hydrazinecarboxylate (28 g) (5.06 g, 18.9mmol) to afford 2.59 g (67% yield) of the intermediate HCI salt as awhite solid. The HCI salt (2.47 g, 12.1 mmol) was then converted to 882mg (43% yield) of freebase 29 g (29% for two steps), isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (bs, 1H), 7.29 (dt, J=6.90, 6.00Hz, 1H), 6.99-7.05 (complex m, 3H), 4.20 (s, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 169.55 (s), 162.52 (d, J_(C,F)=243 Hz), 139.55 (d,J_(C,F)=7.60 Hz), 130.57 (d, J_(C,F)=8.60 Hz), 125.64 (d, J_(C,F)=2.90Hz), 116.19 (d, J_(C,F)=22.1 Hz), 113.72 (d, J_(C,F)=20.2 Hz), 40.55 (d,J_(C,F)=1.90 Hz). LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=1.90 minutes, ESI m/z=169, [M+H]⁺.

Synthesis of 2-(3-Bromophenyl)acetic hydrazide (29h)

Prepared according to the General Procedure 1B tert-butyl2-(2-(3-bromophenyl)acetyl)hydrazinecarboxylate (X28h) (7.41 g, 22.5mmol) to afford 4.00 g (67% yield) of the intermediate HCI salt as awhite solid. The HCI salt (4.00 g, 15.1 mmol) was then converted to 2.73g (79% yield) of freebase 29h (53% for two steps), isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (bs, 1H), 7.43-7.44 (m, 1H),7.37-7.40 (complex m, 1H), 7.20-7.23 (complex m, 2H), 4.26 (bs, 2H).).¹³C NMR (100 MHz, CDCl₃) δ 171.01 (s), 136.28 (s), 132.40 (d), 130.71(d), 130.55 (d), 128.07 (d), 122.99 (s), 41.32 (t). LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=1.98 minutes,ESI m/z=229, [M+H]+; 270, [M+H+ACN]+; 459, [2M+H]+.

Synthesis of 2-(3-(Trifluoromethyl)phenyl)acetic hydrazide (29i)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3-(trifluoromethyl)phenyl)acetyl)hydrazinecarboxylate (28i) (4.20g, 13.2 mmol) to afford 3.26 g (97% yield) of the intermediate HCI saltas a white solid. The HCI salt (3.26 g, 12.8 mmol) was then converted to2.14 g (77% yield) of freebase 29i (75% for two steps), isolated as awhite solid: ¹H NMR (400 MHz, CD₃OD) δ 7.59 (bs, 1H), 7.45-7.54 (m, 3H),3.53 (s, 2H). ¹³C NMR (100 MHz, CD₃OD) δ 170.92, 136.72, 132.61, 130.42(q, J_(C,F)=32.6 Hz), 128.95, 125.42 (q, J_(C,F)=3.80 Hz), 124.30 (q,J_(C,F)=271 Hz), 123.37 (q, J_(C,F)=3.90 Hz), 39.93. LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=2.00 minutes,ESI m/z=219, [M+H]⁺; 437 [2M+1−1]⁺.

Synthesis of 2-(3,5-Difluorophenyl)acetic hydrazide (29j)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3,5-difluorophenyl)acetyl)hydrazinecarboxylate (28j) (3.05 g, 10.7mmol) to afford 2.02 g (85% yield) of the intermediate HCI salt as awhite solid. The HCI salt (1.91 g, 8.58 mmol) was then converted to 740mg (46% yield) of freebase 29j (39% for two steps), isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (bs, 1H), 7.05 (tt, J=9.20, 2.30Hz, 1H), 6.91-6.96 (m, 2H), 4.21 (bs, 1H), 3.36 (s, 2H). ¹³C NMR (100MHz, CDCl₃) δ 170.39 (s), 163.64 (dd, J_(C,F)=249, 13.4 Hz), 137.63 (t,J_(C,F)=8.60 Hz), 112.39 (dd, J_(C,F)=25.9, 7.70 Hz), 103.13 (t,J_(C,F)=24.9 Hz), 41.29 (t, CH₂). LCMS (50-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=1.98 minutes, ESI m/z=229, [M+H]⁺; 270,[M+H+ACN]⁺; 459 [2M+H]⁺.

Synthesis of 2-(3,5-Dichlorophenyl)acetic hydrazide (29k)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3,5-dichlorophenyl)acetyl)hydrazinecarboxylate (28k) (6.00 g, 18.8mmol) to afford 4.34 g (90% yield) of the intermediate HCI salt as awhite solid. The HCI salt (4.34 g, 17.0 mmol) was then converted to 2.65g (71% yield) of freebase 29k (64% for two steps), isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (bs, 1H), 7.42 (t, J=1.90 Hz,1H), 7.27 (d, J=1.90 Hz, 2H), 4.20 (bs, 2H), 3.35 (s, 2H). ¹³C NMR (100MHz, CDCl₃) δ 170.21, 137.21, 135.44, 127.86, 127.83, 40.93. LCMS(50-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=2.10minutes, ESI m/z=219, [M+H]⁺.

Synthesis of 2-(3,4-Dichlorophenyl)acetic hydrazide (29l)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3,4-dichlorophenyl)acetyl)hydrazinecarboxylate (28l) (3.00 g, 9.40mmol) to afford 2.40 g (100% yield) of the intermediate HCI salt as awhite solid. The HCI salt (549 mg, 2.15 mmol) was then converted to 473mg (100% yield) of freebase 29l (100% for two steps), isolated as awhite solid: LCMS (40-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=2.38 minutes, ESI m/z=219, [M+H]⁺.

Synthesis of 2-(1-1,1¹-Biphenyl-4-ypacetic hydrazide (29m)

Prepared according to the General Procedure 1B from tert-butyl2-(2-([1,1′-biphenyl]-4-yl)acetyl)hydrazinecarboxylate (AH.2.182) (3.83g, 11.7 mmol) to afford 2.75 g (89% yield) of the intermediate HCI saltas a white solid. The HCI salt (2.75 g, 10.5 mmol) was then converted to1.84 g (77% yield) of freebase 29m (69% for two steps), isolated as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (bs, 1H), 7.53-7.61 (m,4H), 7.41 (t, J=7.30 Hz, 2H), 7.29-7.32 (m, 3H), 4.19 (bs, 2H), 3.35 (s,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.03, 140.53, 138.86, 136.07,130.05, 129.44, 127.81, 127.08, 127.04, 40.68. LCMS (15-95% acetonitrilein 0.05% TFA over 10 minutes) retention time=6.25 minutes, ESI m/z=227,[M+H]⁺; 453, [2M+H].

Synthesis of 2-phenylacetic hydrazide (29n)

To a solution of methyl phenylacetate (30) (1.00 g, 6.66 mmol) inethanol (50 mL) was added hydrazine hydrate (66.6 mmol). The resultingmixture was heated to reflux for 4 hours. The reaction was cooled andpartitioned with water (200 mL) and EtOAc (200 mL). The EtOAc solutionwas washed again with water (2×200 mL), dried (Na₂SO₄), filtered andconcentrated to afford 370 mg (37% yield) of compound 29n as a viscousoil: ¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (bs, 1H), 7.15-7.27 (m, 5H), 4.17(bs, 2H), 3.30 (s, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.07, 136.81,129.47, 128.70, 126.88, 40.99. LCMS (15-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=3.43 minutes, ESI m/z=151, [M+H]⁺.

General Procedure 1C: Synthesis of Triazoles

A mixture of thioamide (1 mmol) and hydrazide (1.2 mmol) was dissolvedin CH₂Cl₂ (30 mL) and treated with silver benzoate (2 mmol) followedimmediately with acetic acid (3 mmol). The black solution was stirred atroom temperature overnight. The solution was concentrated and theresidue was dissolved in 1:1 MeOH/CH₂Cl₂ and treated with 1N HCl (2mmol). The mixture was stirred for 5 minutes, treated withdiisopropylethylamine (˜10 mmol) and concentrated. The residue wassuspended in MeOH (50 mL), filtered through CELITE (1 inch pad) andconcentrated. The final residue was purified by flash chromatography.

Synthesis of3-(2-(5-(4-Chlorobenzyl)-4-(3-(1-trityl-H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (475 mg, 0.86 mmol) and 2-(4-chlorophenyl)acetic hydrazide (29a)(190 mg, 1.03 mmol). Purification by flash chromatography (SiO₂, 20:1CH₂Cl₂/methanol) afforded 360 mg (61% yield) of compound 31a as a whitesolid: LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=4.35 minutes, ESI m/z=687, [M+H]⁺.

Synthesis of3-(2-(5-(3-Chlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31b)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (200 mg, 0.36 mmol) and 2-(3-chlorophenyl)acetic hydrazide (80.0mg, 0.45 mmol). Purification by flash chromatography (SiO₂, 20:1CH₂Cl₂/methanol) afforded 147 mg (60% yield) of compound 31b as a whitesolid: H NMR (400 MHz, DMSO-d₆) δ 10.83 (bs, 1H), 8.73 (bs, 1H), 7.44(d, J=8.20 Hz, 1H), 7.37-7.42 (m, 10H), 7.21-7.33 (complex multiplets,4H), 7.05-7.15 (complex multiplets, 8H), 7.01 (t, J=8.20 Hz, 1H), 6.90(t, J=8.20 Hz, 1H), 4.20 (s, 2H), 3.89 (distorted triplet, J=7.30 Hz,2H), 3.07-3.16 (m, 4H), 2.53 (distorted t, J=7.30 Hz, 2H), 1.63 (quint,J=7.40 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 155.21 (s), 153.37 (s),140.85 (s), 138.27 (s), 137.71 (s), 133.69 (s), 131.03 (d), 129.68 (d),129.21 (d), 128.14 (d), 127.59 (d), 127.31 (s), 123.42 (d), 121.57 (d),119.97 (s), 118.89 (d), 118.65 (d), 113.07 (s), 111.99 (d), 77.85 (s),43.04 (t), 29.90 (t), 28.15 (t), 25.66 (t), 22.39 (t), 21.88 (t). LCMS(50-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=4.38minutes, ESI m/z=687, [M+H]⁺.

Synthesis of3-(2-(5-(2-Chlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31c)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (500 mg, 0.90 mmol) and 2-(2-chlorophenyl)acetic hydrazide (199 mg,1.08 mmol). Purification by flash chromatography (SiO₂, 20:1CH₂Cl₂/methanol) afforded 286 mg (46% yield) of compound 31c as a whitesolid: LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=3.90 minutes, ESI m/z=687, [M+H]⁺.

Synthesis of3-(2-(5-(4-Methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-5-yl)propyl)-4H-1,2,4-triazol-3-yl)-ethyl)-1H-indole(31d)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (540 mg, 0.97 mmol) and 2-(4-methoxy-phenyl)acetic hydrazide (209mg, 1.16 mmol). Purification by flash chromatography (SiO₂, 30:1 to 20:1CH₂Cl₂/methanol) afforded 250 mg (38% yield) of compound 31d as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (bs, 1H), 6.73-7.91 (complexmultiplets, 25H), 6.51 (s), 3.93 (s, 2H), 3.63 (apparent t, J=7.40 Hz,2H), 3.61 (s, 3H), 3.05 (apparent t, J=7.40 Hz, 2H), 2.89 (apparent t,J=6.90 Hz, 2H), 2.29 (t, J=6.90 Hz, 2H), 1.54 (quint, J=7.30 Hz, 2H).¹³C NMR (100 MHz, DMSO-d₆) δ 158.44 (s), 154.46 (s), 153.21 (s), 142.82(s), 140.16, 138.30, 136.67, 130.51, 129.90, 129.66 (d), 128.95, 128.69(d), 128.46, 127.43, 123.08, 121.40, 118.72, 118.19, 114.38, 114.14,113.87, 111.84, 74.88 (s), 55.49 (q), 42.43 (t), 29.92 (t), 29.55 (t),25.88 (t), 25.05 (t), 23.22 (t). LCMS (25-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=6.75 minutes, ESI m/z=683, [M+H]⁺.

Synthesis of3-(2-(5-(3-Methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl))-1H-indole(31e)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (500 mg, 0.90 mmol) and 2-(3-methoxyphenyl)acetic hydrazide (195mg, 1.08 mmol). Purification by flash chromatography (SiO₂, 20:1 to 10:1CH₂Cl₂/methanol) afforded 190 mg (31% yield) of compound 31e as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 7.99 (bs, 1H), 7.49 (d, J=7.80 Hz, 1H),7.27-7.34 (complex multiplets, 10H), 7.21 (d, J=8.30 Hz, 1H), 6.99-7.11(complex multiplets, 9H), 6.86 (d, J=2.30 Hz, 1H), 6.65-6.68 (m, 3H),6.36 (s, 1H), 4.05 (s, 2H), 3.32 (apparent t, J=7.80 Hz, 2H), 3.26 (t,J=7.80 Hz, 2H), 2.97 (t, J=7.80 Hz, 2H), 2.25 (t, J=7.30 Hz, 2H), 1.51(quint, J=7.80 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 159.91 (s), 155.16(s), 152.17 (s), 142. 41 (s), 138.49, 137.61, 136.22 129.79, 129.77,128.20, 128.17, 122.08, 122.00, 120.92, 119.50, 118.62, 118.14, 114.77,114.16, 112.52, 111.24, 75.33 (s), 55.35 (q), 42.72 (t), 31.70 (t),29.42 (t), 26.20 (t), 25.20 (t), 23.68 (t). LCMS (25-95% acetonitrile in0.05% TFA over 10 minutes) retention time=6.78 minutes, ESI m/z=683,[M+H]⁺.

Synthesis of3-(2-(5-(2-Methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31f)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (500 mg, 0.90 mmol) and 2-(2-methoxyphenyl)acetic hydrazide (195mg, 1.08 mmol). Purification by flash chromatography (SiO₂, 30:1 to 20:1CH₂Cl₂/methanol) afforded 203 mg (33% yield) of compound 31f as a whitesolid: LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=3.70 minutes, ESI m/z=683, [M+H]⁺.

Synthesis of3-(2-(5-(3-Fluorobenzyl)-4-(3-(1-trityl-1H-imidazol-5-0propyl)-4H-1,2,4-triazol-3-yl)-ethyl)-1H-indole(31q)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (514 mg, 0.93 mmol) and 2-(3-fluorophenyl)acetic hydrazide (188 mg,1.11 mmol). Purification by flash chromatography (SiO₂, 20:1CH₂Cl₂/methanol) afforded 300 mg (49% yield) of compound 31g as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) contains minor inseparable aromaticimpurity related to the previous use of Lawesson's reagent,hydrogen-bonded forms observed, major form: δ 10.74 (bs, 1H), 9.20 (bs,0.5H), 7.90 (d, J=6.40 Hz, 1H), 7.58 (t, J=6.40 Hz, 0.5H), 6.90-7.46(complex multiplets, 23H), 6.84 (t, J=7.70 Hz, 1H), 6.48 (s, 1H), 4.05(s, 2H), 3.69 (apparent t, J=8.20 Hz, 2H), 3.06 (apparent t, J=7.55 Hz,2H), 2.91 (apparent, t, J=7.55 Hz, 2H), 2.30 (apparent t, J=6.90 Hz,1H), 1.52 (quint., J=7.30 Hz, 2H). LCMS (25-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=6.82 minutes, ESI m/z=671, [M+H]⁺.

Synthesis of3-(2-(5-(3-Bromobenzyl)-4-(3-(1-trityl-1H-imidazol-5-yl)propyl)-4H-1,2,4-triazol-3y)ethyl)-1H-indole(31h)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamid(10) (748 mg, 1.40 mmol) and 2-(3-bromophenyl)acetic hydrazide (371 mg,1.62 mmol). Purification by flash chromatography (SiO₂, 20:1CH₂Cl₂/methanol) afforded 492 mg (48% yield) of compound 31h as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) contains minor inseparable aromaticimpurity related to the previous use of Lawesson's reagent,hydrogen-bonded forms observed, major form: δ 10.75 (bs, 1H), 7.90 (d,J=6.80 Hz, 1H), 6.98-7.47 (complex multiplets, 23H), 6.84 (t, J=8.00 Hz,1H), 6.49 (s, 1H), 4.03 (s, 2H), 3.70 (apparent t, J=8.20 Hz, 2H),3.05-3.07 (m, 2H), 2.89-2.933 (m, 2H), 2.28-2.32 (m, 2H), 1.51 (quint.,J=7.30 Hz, 2H). LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=4.30 minutes, ESI m/z=731, [M+H]⁺.

Synthesis of 3-(2-(5-(3-(Trifluoromethyl)benzyl)-4-(3-(1-trityl-1H-imidazol-4-Apropyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31i)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (500 mg, 0.90 mmol) and 2-(3,5-difluorophenyl)acetic hydrazide (236mg, 1.08 mmol). Purification by flash chromatography (SiO₂, 40:1CH₂Cl₂/methanol to 20:1) afforded 279 mg (36% yield) of compound 31i asa white solid: LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=4.90 minutes, ESI m/z=721, [M+H]⁺.

Synthesis of 3-(2-(5-(3,5-Difluorobenzyl)-4-(3-(1-trityl-H-imidazol-5-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(3i)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (500 mg, 0.90 mmol) and 2-(3,5-difluorophenyl)acetic hydrazide (206mg, 1.10 mmol). Purification by flash chromatography (SiO₂, 20:1CH₂Cl₂/methanol) afforded 300 mg (47% yield) of compound 31j as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) conformational forms present; majorform: δ 10.74 (bs, 1H), 7.89-7.91 (m, 1H), 7.40 (d, J=8.20 Hz, 1H),7.29-7.33 (complex multiplets, 9H), 7.26 (d, J=7.80 Hz, 1H), 7.19 (d,J=1.30 Hz, 1H), 7.08 (d, J=2.30 Hz, 1H), 6.07-7.01 (complex multiplets,8H), 6.86-6.89 (m, 1H), 6.83 (t, J=6.80 Hz, 1H), 6.51 (s, 1H), 4.07 (s,2H), 3.72 (apparent t, J=6.30 Hz, 2H), 3.06 (apparent t, J=6.90 Hz, 2H),2.92 (apparent t, J=6.40 Hz, 2H), 2.33 (t, J=6.90 Hz, 2H), 1.58 (quint,J=7.80 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 162.79 (dd, J_(C,F)=246,13.4 Hz), 154.70 (s), 152.14 (s), 142.81 (s), 141.82 (t, J_(C,F)=9.50Hz), 140.15, 138.30, 136.68, 129.77, 129.65 (d), 129.06, 128.69 (d),128.45, 127.43, 123.08, 121.40, 118.71, 118.68, 118.13, 113.88, 112.35(dd, J_(C,F)=18.2, 6.70 Hz), 111.85, 102.70 (t, J_(C,F)=24.9 Hz), 74.87(s), 42.51 (t), 30.17 (t), 29.67 (t), 25.91 (t), 24.99 (t), 23.17 (t).LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=4.13 minutes, ESI m/z=689, [M+H]⁺.

Synthesis of3-(2-(5-(3,5-Dichlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31k)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (500 mg, 0.90 mmol) and 2-(3,5-difluorophenyl)acetic hydrazide (237mg, 1.08 mmol). Purification by flash chromatography (SiO₂, 20:1CH₂Cl₂/methanol) afforded 378 mg (58% yield) of compound 31k as a whitesolid: LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=5.25 minutes, ESI m/z=721, [M+H]⁺.

Synthesis of3-(2-(5-(1-1,11-Biphenyl]-4-ylmethyl)-4-(3-(1-trityl-H-imidazol-4-Apropyl)-4H-1,2,4-triazol-3-yl)ethyl))-1H-indole(31m)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (500 mg, 0.90 mmol) and 2-([1,1′-biphenyl]-4-yl)acetic hydrazide(244 mg, 1.08 mmol). Purification by flash chromatography (SiO₂, 20:1CH₂Cl₂/methanol) and recrystallization of the product from ACN afforded235 mg (36% yield) of compound 31m as a white solid: ¹H NMR (400 MHz,DMSO-d₆) δ 10.71 (bs, 1H), 7.54 (d, J=7.40 Hz, 2H), 7.48 (d, J=8.20 Hz,2H), 7.35-7.43 (m, 3H), 7.25-7.31 (complex m, 11H), 7.16-7.19 (complexm, 3H), 7.07 (d, J=2.30 Hz, 1H), 6.96-6.98 (m, 7H), 6.85 (t, J=7.30 Hz,1H), 6.50 (s, 1H), 4.05 (s, 2H), 3.68 (apparent t, J=8.20 Hz, 2H), 3.07(apparent t, J˜7.55 Hz, 2H), 2.92 (apparent t, J˜7.80 Hz, 2H), 2.32 (t,J=6.90 Hz, 2H), 1.61 (quint, J=7.80 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆)δ 154.54, 152.84, 142.81, 140.34, 140.18, 139.05, 138.31, 136.72,136.47, 130.11, 129.65, 129.48, 129.39, 128.65, 128.42, 127.85, 127.47,127.28, 127.06, 123.10, 121.39, 118.73, 118.69, 118.20, 113.90, 111.85,74.90, 42.53, 30.40, 29.60, 25.95, 25.06, 23.28. LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=5.40 minutes,ESI m/z=729, [M+H]⁺.

Synthesis of3-(2-(5-Benzyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl))-1H-indole31n)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (580 mg, 1.04 mmol) and 2-phenylacetic hydrazide (187 mg, 1.24mmol). Purification by flash chromatography (SiO₂, 20:1 CH₂Cl₂/methanol)afforded 310 mg (46% yield) of compound 31n as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 10.74 (bs, 1H), 9.18 (bs, 1H), 7.90 (d, J=6.90 Hz,1H), 6.98-7.55 (complex multiplets, 24H), 6.84 (t, J=6.80 Hz, 1H), 6.45(s, 1H), 4.01 (s, 2H), 3.65 (apparent t, J=8.30 Hz, 2H), 3.06 (apparentt, J=8.20 Hz, 2H), 2.90 (apparent t, J=7.80 Hz, 2H), 2.27 (t, J=7.30 Hz,2H), 1.47 (quint., J=7.40 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.54(s), 152.95 (s), 142.83 (s), 140.17, 138.26, 137.28, 136.81, 136.69,133.35, 129.79, 129.68 (d), 129.47, 129.09, 128.98, 128.90, 128.70 (d),128.48, 127.45, 127.08, 126.88, 123.10, 121.41, 118.74, 118.71, 118.16,113.90, 111.86, 74.88 (s), 42.51 (t), 40.99 (t), 30.77 (t), 29.58 (t),25.91 (t), 25.09 (t), 23.22 (t). LCMS (50-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=3.97 minutes, ESI m/z=653, [M+H]⁺.

Synthesis of (R)-tert-butyl(1-(5-(3-chlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-0-2-(1H-indol-3-yl)ethyl)carbamate(33)

Prepared according to the General Procedure 1C from (R)-tert-butyl(3-(1H-indol-3-0-1-thioxo-1-((3-(1-trityl-1H-imidazol-4-Apropyl)amino)propan-2-yl)carbamate(26) (289 mg, 0.43 mmol) and 2-(3-chlorophenyl)acetic hydrazide (95.6mg, 0.52 mmol). Purification by flash chromatography (SiO₂, 20:1CH₂Cl₂/methanol) afforded 80 mg (23% yield) of compound 33 as a tanfoam: LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=5.90 minutes, ESI m/z=802, [M+H]⁺.

Synthesis of3-(2-(5-(3,4-Dichlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1-methyl-1H-indole(35)

Prepared according to the General Procedure 1C from3-(1-methyl-1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(14) (440 mg, 0.77 mmol) and 2-(3,4-Dichlorophenyl)acetic hydrazide(29l) (203 mg, 0.93 mmol). Purification by flash chromatography (SiO₂,40:1 CH₂Cl₂/methanol to 20:1) and recrystallization of the product fromACN afforded 390 mg (67% yield) of compound 35 as a white solid: LCMS(50-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=5.62minutes, ESI m/z=735, [M+H]⁺.

Synthesis of1-Methyl-3-(2-(5-(3-(trifluoromethyl)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(37)

Prepared according to the General Procedure 1C from3-(1-methyl-1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(14) (720 mg, 1.26 mmol) and 2-(3-(trifluoromethyl)phenyl)acetichydrazide (29i) (331 mg, 1.52 mmol). Purification by flashchromatography (SiO₂, 40:1 CH₂Cl₂/methanol to 20:1) afforded 463 mg (50%yield) of compound 37 as a white solid: LCMS (50-95% acetonitrile in0.05% TFA over 10 minutes) retention time=5.47 minutes, ESI m/z=735,[M+H]⁺.

General Procedure 1D: Trityl Deprotection

A mixture of the trityl-protected compound (1 mmol) in ethanol (50 mL)was added 2N HCI (25 mL) and the mixture was heated to 70° C. for 2-4hours. The reaction was cooled, transferred to a separatory funnel, anddiluted with water (50 mL). The solution was washed with CH₂Cl₂ (3×50mL). The resulting aqueous solution was made basic with 2N NaOH (checkedwith pH paper) and extracted with CH₂Cl₂ (3×50 mL). The combinedextracts were dried (Na₂SO₄), filtered and concentrated. The residue waspurified by recrystallization, flash chromatography, or used as is.

Synthesis of342444341H-Imidazol-4-yl)propyl)-5-(4-chlorobenzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(BN-VI-62)

Prepared according to the General Procedure 1D from3-(2-(5-(2-chlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31a) (257 mg, 0.37 mmol) to afford 114 mg (69% yield) of BN-VI-62 as awhite solid: LCMS (25-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=5.43 minutes, ESI m/z=445, [M+H]⁺.

Synthesis of3-(2-(4-(3-(1H-Imidazol-4-yl)propyl)-5-(3-chlorobenzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(BN-VI-56)

Prepared according to the General Procedure 1D from3-(2-(5-(3-chlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-ypethyl)-1H-indole(31b) (48.0 mg, 0.07 mmol) to afford 27.0 mg (87% yield) of BN-VI-56 asa white solid: LCMS (25-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=5.38 minutes, ESI m/z=445, [M+H]⁺.

Synthesis of3-(2-(4-(3-(1H-Imidazol-4-yl)propyl)-5-(2-chlorobenzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(MM-I-17)

Prepared according to the General Procedure 1D from3-(2-(5-(2-chlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-ypethyl)-1H-indole(31c) (234 mg, 0.34 mmol). Recrystallization from ACN afforded 76.0 mg(50% yield) of MM-I-17 (Example 3) as a white solid: ¹H NMR (400 MHz,DMSO-d₆) imidazole tautomers observed: δ 11.77 and 11.70 (twooverlapping bs, 1H overall), 10.78 (bs, 1H), 7.41-7.44 (m, 3H), 7.29 (d,J=8.20 Hz, 1H), 7.22-7.27 (m, 2H), 7.06-7.10 (complex multiplet, 2H),7.02 (t, J=7.30 Hz, 1H), 6.92 (t, J=7.30 Hz, 1H), 6.71 and 6.51 (twobroadened singlets, 1H overall), 4.08 (s, 2H), 3.68-3.78 (m, 2H),3.05-3.08 (m, 2H), 2.94-2.98 (m, 2H), 2.36 (t, J=6.90 Hz, 2H), 1.71(quint, J=7.30 Hz, 2H). LCMS (15-95% acetonitrile in 0.05% TFA over 10minutes) retention time=5.98 minutes, ESI m/z=445, [M+H]⁺.

Synthesis of3-(2-(4-(3-(1H-Imidazol-4-0propyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(SM-I-29)

Prepared according the General Procedure 1D rom3-(2-(5-(4-methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31d) (210 mg, 0.30 mmol) to afford 110 mg (83% yield) of SM-I-29 as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) imidazole tautomers observed: δ11.73 (bs, 1H), 10.77 (bs, 1H), 7.49 and 7.45 (2 bs, 1H overall), 7.42(d, J=7.40 Hz, 1H), 7.11-7.34 (complex multiplets, 5H), 7.09 (d, J=2.30Hz, 1H), 7.02 (dt, J=6.60, 0.90 Hz, 1H), 6.97 (d, J=8.30 Hz, 2H), 6.92(t, J=6.90 Hz, 1H), 6.78-6.81 (m, 2H), 6.69 and 6.50 (2 bs, 1H overall),3.93 (s, 2H), 3.66 (s, 3H), 3.60-3.66 (m, 2H), 3.06 (apparent t, J=8.20Hz, 2H), 2.91 (apparent t, J=6.90 Hz, 2H), 2.29-2.38 (m, 2H), 1.53-1.62(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) imidazole tautomers observed: δ158.48 (s), 154.53 (s), 153.24 (s), 148.29, 144.63, 139.80, 136.68,135.20, 130.43, 129.91, 128.93, 128.65, 128.41, 128.29, 128.06, 127.45,127.17, 123.11, 121.43, 118.80, 118.71, 114.45, 114.2, 113.90, 112.55,111.86, 55.54 (q), 42.49 (t), 42.34 (t), 29.99 (t), 29.90 (t), 29.52(t), 25.88 (t), 25.00 (t), 23.26 (t), 23.18 (t). LCMS (5-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=6.30 minutes,ESI m/z=441, [M+H]⁺.

Synthesis of3-(2-(4-(3-(1H-Imidazol-4-yl)propyl)-5-(3-methoxybenzyl)-4H-1,2,4-triazol-3-Methyl)-1H-indole(BN-VI-61)

Prepared according to the General Procedure 1D rom3-(2-(5-(3-methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-ypethyl)-1H-indole(31e) (177 mg, 0.26 mmol) to afford 96 mg (84% yield) of BN-VI-61 as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (bs, 1H), 10.78 (bs, 1H),7.49 (s, 1H), 7.43 (d, J=7.80 Hz, 1H), 7.29 (d, J=7.80 Hz, 1H), 7.15 (t,J=7.80 Hz, 1H), 7.10 (d, J=1.80 Hz, 1H), 7.02 (t, J=7.40 Hz, 1H), 6.92(t, J=7.40 Hz, 1H), 6.72-6.76 (m, 2H), 6.62-6.68 (m, 2H), 3.99 (s, 2H),3.69 (apparent t, J=7.40 Hz, 2H), 3.07 (apparent t, J=6.90 Hz, 2H), 2.92(apparent t, J=6.90 Hz, 2H), 2.34 (t, J=6.80 Hz, 2H), 1.59 (quint,J=7.80 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.88 (s), 154.57 (s),152.91 (s), 138.74, 136.71, 135.19, 130.13, 127.47, 123.10, 121.45,121.11, 118.81, 118.73, 114.69, 113.94, 112.55, 111.88, 55.50 (q), 42.50(t), 30.79 (t), 29.74 (t), 25.91 (t), 23.19 (t). LCMS (25-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=4.02 minutes,ESI m/z=441, [M+H]⁺.

Synthesis of342444341H-Imidazol-4-yl)propyl)-5-(2-methoxybenzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(MM-I-21)

Prepared according to the General Procedure 1D from3-(2-(5-(2-methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-ypethyl)-1H-indole(31f) (102 mg, 0.15 mmol) to afford 21 mg (74% yield) of MM-I-21 as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) imidazole tautomers observed: δ11.75 and 11.69 (two overlapping bs, 1H overall), 10.77 (bs, 1H),7.41-7.44 (m, 2H), 7.29 (d, J=8.30 Hz, 1H), 7.18 (broadened dt, J=6.40,1.80 Hz, 1H), 7.09 (d, J=1.80 Hz, 1H), 7.02 (dt, J=6.90, 0.9 Hz, 1H),6.90-6.95 (m, 2H), 6.80-6.88 (m, 3H), 6.69 and 6.50 (two bs, 1Hoverall), 3.92 and 3.91 (two overlapping s, 2H overall), 3.73 and 3.72(two overlapping s, 3H overall), 3.64-3.73 (m, 2H), 3.04-3.09 (m, 2H),2.91-2.95 (m, 2H), 2.38 and 2.33 (two t, J=7.80 and 6.90 Hz,respectively, 2H overall), 1.61-1.70 (m, 2H). LCMS (15-95% acetonitrilein 0.05% TFA over 10 minutes) retention time=5.95 minutes, ESI m/z=441,[M+H]⁺.

Synthesis of342444341H-Imidazol-4-yl)propyl)-5-(3-fluorobenzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(SM-I-38)

Prepared according to the General Procedure 1D from3-(2-(5-(3-fluorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31 g) (290 mg, 0.43 mmol) to afford 120 mg (65% yield) of SM-I-38 as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) imidazole tautomers observed: δ11.75 and 9.21 (two bs, 1H overall), 10.78 (bs, 1H), 7.47 (s, 1H), 7.42(d, J=7.70 Hz, 1H), 7.29 (apparent q, J=7.80 Hz, 2H), 7.10 (bs, 1H),6.97-7.05 (m, 3H), 6.89-6.95 (m, 2H), 6.65 (bs, 1H), 4.05 (s, 2H), 3.70(apparent t, J=7.80 Hz, 2H), 3.07 (apparent t, J=7.55 Hz, 2H), 2.93(apparent t, J=7.55 Hz, 2H), 2.35 (t, J=6.90 Hz, 2H), 1.61 (quint,J=7.30 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) imidazole tautomers observed:δ 162.68 (d, J_(C,F)=243 Hz), 162.68 (d, J_(C,F)=243 Hz), (s), 154.68(s), 152.56 (s), 140.07 (d, J_(C,F)=7.60 Hz), 139.54 (d, J_(C,F)=7.60Hz), 136.60, 135.21, 130.99 (d, J_(C,F)=8.70 Hz), 130.55 (d,J_(C,F)=8.70 Hz), 127.45, 125.63, 125.09, 123.11, 121.44, 118.79,118.70, 116.18 (d, J_(C,F)=22.1 Hz), 115.82 (d, J_(C,F)=21.1 Hz),114.12, 113.91, 113.71 (d, J_(C,F)=21.1 Hz), 111.87, 42.27 (t), 31.22(t), 30.35 (t), 29.81 (t), 25.92 (t), 23.2 (t). LCMS (40-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=1.88 minutes,ESI m/z=429, [M+H]⁺.

Synthesis of342444341H-Imidazol-4-yl)propyl)-5-(3-bromobenzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(SM-I-50)

Prepared according to the General Procedure 1D from3-(2-(5-(3-(bromobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31h) (270 mg, 0.37 mmol) to afford 100 mg (55% yield) of SM-I-50 as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) major tautomer δ 11.75 (bs, 1H),10.77 (bs, 1H), 7.48 (s, 1H), 7.42 (d, J=8.30 Hz, 1H), 7.38-7.40 (m,2H), 7.15 7.34 (complex multiplets, 5H), 7.08-7.11 (m, 2H), 7.02 (t,J=6.90 Hz, 1H), 6.91 (t, J=7.30 Hz, 1H), 6.66 (bs), 4.04 (s, 2H), 3.71(apparent t, J=7.70 Hz, 2H), 3.07 (apparent t, J=7.55 Hz, 2H), 2.93(apparent t, J=7.55 Hz, 2H), 2.36 (t, J=7.30 Hz, 2H), 1.62 (quint,J=7.80 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) major tautomer δ 154.67 (s),152.57 (s), 140.02, 136.69, 135.20, 131.81, 131.16, 130.08, 128.40,128.29, 128.17, 128.06, 127.45, 123.11, 122.24, 121.44, 118.80, 118.70,113.90, 111.87, 42.48 (t), 30.18 (t), 29.94 (t), 25.91 (t), 23.20 (t).LCMS (5-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=6.47 minutes, ESI m/z=489, [M+H]⁺.

Synthesis of 3-(2-(4-(3-(1H-Imidazol-4-yl)propyl)-5-(3-(trifluoromethyl)benzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole (BN-VI-97)

Prepared according to the General Procedure 1D from3-(2-(5-(3-(trifluoromethyl)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31i) (268 mg, 0.37 mmol) to afford 121 mg (68% yield) of BN-VI-97 as awhite solid: ¹H NMR (400 MHz, DMSO-d₆, 80° C.) imidazole tautomersobserved δ 11.54 and 9.06 (2 bs, 1H overall), 10.56 (bs, 1H), 7.58 (s,1H), 7.48-7.55 (m, 3H), 7.41-7.44 (m, 2H), 7.30 (d, J=8.20 Hz, 1H), 7.07(s, 1H), 7.02 (t, J=6.80 Hz, 1H), 6.92 (t, J=7.80 Hz, 1H), 6.66 (bs,1H), 4.14 (s, 2H), 3.71-3.79 (m, 2H), 3.10 (apparent t, J=6.80 Hz, 2H),2.96 (apparent t, J=7.30 Hz, 2H), 2.36-2.41 (m, 2H), 1.69 (b quint,J˜6.50 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆, 80° C.) imidazole tautomersobserved δ 156.06, 152.63, 136.92, 136.67, 134.83, 131.88, 130.72 (q,J_(C,F)=32.6 Hz), 129.46, 126.97, 124.91 (q, J_(C,F)=3.80 Hz), 124.14(q, J_(C,F)=271 Hz), 123.68 (q, J_(C,F)=3.80 Hz), 122.13, 121.10,118.46, 117.62, 112.91, 111, 42.08, 29.93, 28.79, 25.81, 23.66. LCMS(5-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=6.58minutes, ESI m/z=479, [M+H]⁺.

Synthesis of 3-(2-(4-(3-(1H-Imidazol-4-yl)propyl)-5-(3,5-difluorobenzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole (SM-I-55)

Prepared according to the General Procedure 1D from3-(2-(5-(3,5-difluorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31j) (250 mg, 363 mmol) to afford 130 mg (80% yield) of SM-I-55 as awhite solid. A small fraction was recrystallized from ACN to afford purematerial: ¹H NMR (400 MHz, DMSO-d₆) imidazole tautomers observed δ 11.74(bs, 1H), 10.77 (bs, 1H), 7.48 (bs, 1H), 7.41 (d, J=7.70 Hz, 1H), 7.28(d, J=8.30 Hz, 1H), 7.05-7.11 (m, 2H), 7.01 (t, J=7.40 Hz, 1H),6.86-6.92 (m, 3H), 6.72 and 6.51 (two bs, 1H overall), 4.07 (s, 2H),3.66-3.76 (m, 2H), 3.05-3.08 (m, 2H), 2.92-2.95 (m, 2H), 2.33-2.37 (m,2H), 1.59-1.68 (m, 2H). LCMS (5-95% acetonitrile in 0.05% TFA over 10minutes) retention time=6.40 minutes, ESI m/z=447, [M+H]⁺.

Synthesis of3-(2-(4-(3-(1H-Imidazol-4-yl)propyl)-5-(3,5-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(BN-VI-89)

Prepared according to the General Procedure 1D from3-(2-(5-(3,5-dichlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31k) (328 mg, 0.45 mmol) to afford 179 mg (83% yield) of BN-VI-89 as anoff white solid: ¹H NMR (400 MHz, DMSO-d₆) imidazole tautomers observedδ 11.73 and 9.19 (2 bs, 1H overall), 10.74 (bs, 1H), 7.40-7.47 (m, 3H),7.25-7.30 (m, 3H), 7.10 (s, 1H), 7.02 (t, J=6.90 Hz, 1H), 6.91 (t,J=6.90 Hz, 1H), 6.72 and 6.58 (2 bs, 1H overall), 4.07 (s, 2H),3.73-3.79 (bm, 2H), 3.08 (apparent t, J=7.40 Hz, 2H), 2.94 (apparent t,J=7.40 Hz, 2H), 2.35-2.42 (bm, 2H), 1.67 (bquint, J=6.80 Hz, 2H). LCMS(25-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=5.82minutes, ESI m/z=479, [M+H]⁺.

Synthesis of3-(2-(4-(3-(1H-Imidazol-4-yl)propyl)-5-(1,1′-biphenyl-4-ylmethyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(MM-I-26)

Prepared according to the General Procedure 1D from3-(2-(5-([1,1′-biphenyl]-4-ylmethyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31k) (204 mg, 0.28 mmol) to afford 36 mg (26% yield) of MM-I-26 as awhite solid: ¹H NMR (400 MHz, CD₃OD) δ 7.51-7.54 (complex m, 3H), 7.47(d, J=7.30 Hz, 2H), 7.39 (t, J=7.40 Hz, 2H), 7.28-7.32 (m, 2H), 7.26 (d,J=7.80 Hz, 1H), 7.01-7.06 (m, 1H), 7.00 (d, J=8.30 Hz, 2H), 6.92 (dt,J=7.80 Hz, 1H), 6.89 (s, 1H), 6.53 (bs, 1H), 4.03 (s, 2H), 3.31(apparent t, J=7.30 Hz, 2H), 3.81 (apparent t, J=6.90 Hz, 2H), 3.01(apparent t, J=6.90 Hz, 2H), 2.25 (t, J=7.30 Hz, 2H), 1.38 (apparentquint, J˜7.80 Hz, 2H). ¹³C NMR (100 MHz, CD₃OD) δ 156.03, 153.15,140.44, 140.06, 136.67, 135.99 (broadened), 134.73, 134.38, 129.21,128.53, 128.46, 127.13, 127.09, 126.55, 122.19, 121.10, 118.50, 117.68,115.68, 112.90, 111.00, 42.19, 30.05, 28.68, 25.77, 23.68, 23.13. LCMS(15-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=6.30minutes, ESI m/z=487, [M+H]⁺.

Synthesis of342444341H-Imidazol-4-yl)propyl)-5-benzyl-4H-1,2,4-triazol-3-ypethyl)-1H-indole(S M-I-26)

Prepared according to the General Procedure 1D from3-(2-(5-benzyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31n) (250 mg, 0.38 mmol). Recrystallization from ACN afforded 46.0 mg(30% yield) of SM-I-26 as a white solid: H NMR (400 MHz, DMSO-d₆)imidazole tautomers observed: δ 11.74 and 9.18 (2 bs, 1H overall), 10.77(bs, 1H), 7.47 (s, 1H), 7.42 (d, J=8.20 Hz, 1H), 7.15-7.30 (complex m,5H), 7.06-7.10 (m, 3H), 7.02 (t, J=7.30 Hz, 1H), 6.91 (t, J=7.40 Hz,1H), 6.67 and 6.53 (2 bs, 1H overall), 4.01 (s, 2H), 3.62-3.69 (bm, 2H),3.06 (apparent t, J˜7.55 Hz, 2H), 2.92 (apparent t, J˜7.80 Hz, 2H),2.30-2.35 (bm, 2H), 1.53-1.64 (bm, 2H). ¹³C NMR (100 MHz, DMSO-d₆)imidazole tautomers observed: δ 154.58, 152.95, 137.18, 136.68, 135.19,129.46, 129.05, 128.91, 128.69, 127.45, 127.13, 126.87, 123.11, 121.43,118.80, 118.71, 113.90, 111.87, 42.45, 30.81, 29.78 (broadened), 25.90,24.86 (broadened), 23.22. LCMS (15-95% acetonitrile in 0.05% TFA over 10minutes) retention time=5.88 minutes, ESI m/z=411, [M+H]⁺.

Synthesis of(R)-1-(4-(3-(1H-Imidazol-4-yl)propyl)-5-(3-chlorobenzyl)-4H-1,2,4-triazol-3-VI)-2-(1H-indol-3-yl)ethanamine(BN-VI-87)

Prepared according to the General Procedure 1D from (R)-tert-butyl(1-(5-(3-chlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)carbamate(33) (80.0 mg, 0.10 mmol) to afford 32 mg (72% yield) of BN-VI-87 as atan foam: LCMS (25-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=3.00 minutes, ESI m/z=460, [M+H]⁺.

Synthesis of3-(2-(4-(3-(1H-Imidazol-4-yl)propyl)-5-(3,4-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1-methyl-IH-indole (SM-I-60)

Prepared according to the General Procedure 1D from3-(2-(5-(3,4-dichlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1-methyl-1H-indole(35) (320 mg, 0.44 mmol) to afford 120 mg (56% yield) of SM-I-60 as awhite foam: ¹H NMR (400 MHz, DMSO-d₆) imidazole tautomers observed δ11.75 and 9.20 (2 bs, 1H overall), 7.52 (d, J=8.20 Hz, 1H), 7.47-7.49(bm, 1H), 7.45 (d, J=1.80 Hz, 1H), 7.41 (d, J=7.80 Hz, 1H), 7.32 (d,J=8.20 Hz, 1H), 7.05-7.12 (complex m, 3H), 6.94 (t, J=7.40 Hz, 1H), 6.66(bs, 1H), 4.05 (s, 2H), 3.65-3.72 (m, 2H), 3.66 (s, 3H), 3.05 (apparentt, J˜7.55 Hz, 2H), 2.91 (apparent t, J˜7.55 Hz, 2H), 2.36 (t, J=7.30 Hz,2H), 1.61 (quint, J=7.30 Hz, 2H). LCMS (15-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=6.45 minutes, ESI m/z=493, [M+H]⁺.

Synthesis of 3-(2-(4-(3-(1H-imidazol-4-0propyl)-5-(3-(trifluoromethyl)benzyl)-4H-1,2,4-triazol-3-yl)ethyl)-I-methyl-1H-indole(SM-I-76)

Prepared according to General Procedure 1D from1-methyl-3-(2-(5-(3-(trifluoromethyl)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3yl)ethyl)-1H-indole(37) (0.620 g, 0.843 mmol) to afford 0.220 g (77% yield) of compoundSM-I-76 as a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.53-7.51 (m, 2H),7.46-7.42 (m, 2H), 7.28 (d, J=8.00 Hz, 1H), 7.24-7.22 (m, 2H), 7.10 (dt,J=7.00, 0.84 Hz, 1H), 6.93 (dt, J=7.23, 0.78 Hz, 1H), 6.77 (s, 1H), 6.55(bs, 1H), 4.09 (s, 2H), 3.60 (s, 3H), 3.35-3.31 (m, 2H), 3.15 (t, J=7.15Hz, 2H), 3.00 (t, J=6.79 Hz, 2H), 2.26 (t, J=7.07 Hz, 2H), 1.41 (quint.,J=7.18 Hz, 2H). ¹³C NMR (100 MHz, CD₃OD) δ 155.98, 152.66, 137.13,136.96, 134.85, 131.97, 130.74 (q, J_(C,F)=32.2 Hz), 129.48, 127.48,126.56, 124.92 (q, J_(C,F)=3.76 Hz), 124.14 (q, J_(C,F)=271.3 Hz),123.71 (q, J_(C,F)=3.73 Hz), 121.24, 118.53, 117.96, 112.42, 108.93,42.13, 31.25, 29.94, 28.75, 25.87, 23.47, 23.15. LCMS (25-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=5.98 minutes,ESI m/z=493, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-benzyl-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(SK-I-25)

Prepared according to General Procedure 1D from3-((5-benzyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(237 mg, 0.37 mmol) to afford 113 mg (77% yield) of compound SK-I-25 asa white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.53 (s, 1H), 7.35 (d, J=7.92Hz, 1H), 7.30 (d, J=8.21 Hz, 1H), 7.23-7.14 (complex m, 3H), 7.06 (dt,J=7.11, 0.66 Hz, 1H), 7.02 (d, J=6.89, 2H), 6.94 (apparent t, J=6.83 Hz,2H), 6.51 (s, 1H), 4.25 (s, 2H), 4.06 (s, 2H), 3.59 (apparent t, J=8.33Hz, 2H), 2.24 (t, J=7.07 Hz, 2H), 1.35 (quint., J=7.21 Hz, 2H). ¹³C NMR(100 MHz, CD₃OD) δ 154.82, 154.21, 136.84, 135.41, 134.66, 128.59,128.01, 126.89, 126.66, 122.96, 121.51, 118.83, 117.88, 111.16, 107.93,42.75, 30.37, 28.88, 23.18, 21.55. LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=1.75 minutes, ESI m/z=397, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(SK-I-16)

Prepared according to General Procedure 1D from3-((5-(4-fluorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(150 mg, 0.23 mmol) to afford 86 mg (91% yield) of compound SK-I-16 as awhite solid: ¹H NMR (400 MHz, CD₃OD) δ 7.53 (s, 1H), 7.34 (d, J=8.02 Hz,1H), 7.30 (d, J=8.23 Hz, 1H), 7.28-7.25 (m, 1H), 4.26 (s, 2H), 4.04 (s,2H), 3.63-3.59 (m, 2H), 2.27 (t, J=7.07 Hz, 2H), 1.39 (t, J=7.10 Hz,2H). LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=1.78 minutes, ESI m/z=415, [M+H]⁺

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(4-chlorobenzyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(SK-I-22)

Prepared according to General Procedure 1D from3-((5-(4-chlorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(220 mg, 0.33 mmol) to afford 115 mg (83% yield) of compound SK-I-22 asa white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.54 (s, 1H), 7.34 (d, J=7.91Hz, 1H), 7.30 (d, J=8.07 Hz, 1H), 7.26-7.20 (m, 4H), 7.07 (dt, J=8.01,0.97 Hz, 1H), 7.01 (d, J=8.43 Hz, 2H), 6.96-6.92 (m, 2H), 4.26 (s, 2H),4.04 (s, 2H), 3.63-3.59 (m, 2H), 2.26 (t, J=7.10 Hz, 2H), 1.38 (t,J=7.02 Hz, 2H). LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=1.82 minutes, ESI m/z=431, [M+H]⁺.

Synthesis of 3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3-(trifluoromethyl)benzyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole (MM-I-66)

Prepared according to General Procedure 1D from3-((5-(3-(trifluoromethyl)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(242 mg, 0.34 mmol) to afford 120 mg (75% yield) of compound MM-I-66 asa white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.53-7.49 (m, 2H), 7.45-7.41(m, 2H), 7.32 (m, 3H), 7.06 (dt, J=8.05, 0.79 Hz, 1H), 6.95 (s, 1H),6.93 (t, J=7.30 Hz, 1H), 6.53 (bs, 1H), 4.27 (s, 2H), 4.16 (s, 2H),3.68-3.64 (m, 2H), 2.27 (t, J=7.10 Hz, 2H), 1.40 (quint., J=7.20 Hz,2H). ¹³C NMR (100 MHz, CD₃OD) δ 154.93, 153.61, 136.97, 136.85, 134.73,132.60, 131.99, 130.78 (q, J_(C,F)=31.9 Hz), 129.40, 128.95, 126.65,124.80 (q, J_(C,F)=3.58 Hz), 124.1 (q, J_(C,F)=271.3 Hz), 123.71 (q,J_(C,F)=3.69 Hz), 122.96, 121.51, 118.86, 117.82, 111.17, 107.88, 42.78,29.93, 28.76, 23.22, 21.58. LCMS (50-95% acetonitrile in 0.05% TFA over10 minutes) retention time=2.05 minutes, ESI m/z=465, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3-(trifluoromethyl)benzyl)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-JH-indole(MM-I-87)

Prepared according to General Procedure 1D from6-fluoro-3-((5-(3-(trifluoromethyl)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(125 mg, 0.17 mmol) to afford 60 mg (72% yield) of compound MM-I-87 as awhite solid: ¹H NMR (400 MHz, CD₃OD) δ 7.54 (s, 1H), 7.51 (d, J=7.79 Hz,1H), 7.44 (t, J=7.61 Hz, 1H), 7.42 (s, 1H), 7.34-7.28 (m, 2H), 6.99 (dd,J=9.98, 2.22 Hz, 1H), 6.95 (s, 1H), 6.72 (dt, J=9.63, 2.32 Hz, 1H), 6.57(bs, 1H), 4.25 (s, 2H), 4.17 (s, 2H), 3.70-3.66 (m, 2H), 2.31 (t, J=7.08Hz, 2H), 1.42 (quint., J=7.12 Hz, 2H). ¹³C NMR (100 MHz, CD₃OD) δ (d,J_(C,F)=235.96 Hz), 154.71, 153.67, 136.95, 136.80 (d, J_(C,F)=12.54Hz), 134.77, 132.60, 132.02, 130.78 (q, J_(C,F)=32.24 Hz), 129.42,128.95, 124.80 (q, J_(C,F)=3.70 Hz), 124.10 (q, J_(C,F)=271.45 Hz),123.71 (q, J_(C,F)=3.68 Hz), 123.50 (d, J_(C,F)=2.84 Hz), 123.37,122.74, 118.86, 118.76, 108.20, 107.34 (d J_(C,F)=24.93 Hz), 97.06 (d,J_(C,F)=26.00 Hz), 42.75, 29.92, 29.4228.78, 21.51. LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=2.07 minutes,ESI m/z=483, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3-(methylsulfonyl)benzyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(MM-I-72)

Prepared according to General Procedure 1D from3-((5-(3-(methylsulfonyl)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(65 mg, 0.09 mmol) to afford 37 mg (86% yield) of compound MM-1-72 as awhite solid: ¹H NMR (400 MHz, CD₃OD) δ 7.79 (d, J=7.79 Hz, 1H), 7.71 (s,1H), 7.54 (bs, 1H), 7.51 (t, J=7.75 Hz, 1H), 7.42 (d, J=7.73 Hz, 1H),7.36 (d, J=7.91 Hz, 1H), 7.30 (d, J=8.23 Hz, 1H), 7.06 (dt, J=8.08, 0.84Hz, 1H), 6.97 (s, 1H), 6.95 (dt, J=8.03, 0.77 Hz, 1H), 6.55 (bs, 1H),4.28 (s, 2H), 4.19 (s, 2H), 3.69-3.65 (m, 2H), 2.98 (s, 3H), 2.29 (t,J=7.07 Hz, 2H), 1.41 (t, J=6.95 Hz, 2H). ¹³C NMR (100 MHz, CD₃OD) δ154.97, 153.51, 141.35, 137.51, 136.85, 134.81, 133.64, 129.75, 126.91,126.67, 125.92, 123.02, 121.52, 118.91, 117.85, 111.19, 107.89, 42.89,42, 80, 29.93, 28.84, 23.34, 21.59. LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=1.72 minutes, ESI m/z=475, [M+H]⁺.

Synthesis of3-(2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(3-(methylsulfonyl)benzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(SM-I-92)

Prepared according to General Procedure 1D from3-(2-(5-(3-(methylsulfonyl)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(80 mg, 0.11 mmol) to afford 39 mg (73% yield) of compound SM-I-92 as awhite solid: ¹H NMR (400 MHz, CD₃OD) δ 7.81 (d, J=7.80 Hz, 1H), 7.70 (s,1H), 7.54-7.50 (m, 2H), 7.30-7.25 (m, 4H), 7.04 (t, J=7.31 Hz, 1H), 6.92(t, J=7.69 Hz, 1H), 6.88 (s, 1H), 6.57 (s, 1H), 4.10 (s, 2H), 3.31-3.26(obscured m, 2H), 3.17 (t, J=7.00 Hz, 2H), 3.08-3.01 (m, 1H), 3.05 (s,3H), 2.26 (t, J=7.04 Hz, 2H), 1.44 (quint., J=7.26 Hz, 2H). ¹³C NMR (100MHz, CD₃OD) δ 156.13, 152.45, 141.30, 137.47, 136.64, 134.90, 133.53,129.80, 126.98, 126.91, 125.88, 122.20, 121.13, 118.51, 117.62, 112.85,111.02, 42.90, 42.08, 29.94, 28.81, 25.77, 23.72, 23.15. LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=1.73 minutes,ESI m/z=489, [M+H]⁺

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-benzyl-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(MM-I-89)

Prepared according to General Procedure 1D from3-((5-benzyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(180 mg, 0.27 mmol) to afford 89 mg (78% yield) of compound MM-I-89 as awhite solid: ¹H NMR (400 MHz, CD₃OD) δ 7.55 (bs, 1H), 7.31-7.15 (complexm, 5H), 7.03 (d, J=6.95 Hz, 2H), 7.99 (dd, J=9.89, 2.32 Hz, 1H), 6.93(s, 1H), 6.73 (dt, J=9.69, 2.31 Hz, 1H), 6.55 (bs, 1H), 4.23 (s, 2H),4.07 (s, 2H), 3.63-3.59 (m, 2H), 2.28 (t, J=7.04 Hz, 2H), 1.38 (quint.,J=7.09 Hz, 1H). LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=1.78 minutes, ESI m/z=415, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3-bromobenzyl)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(MM-I-83)

Prepared according to General Procedure 1D from3-((5-benzyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(180 mg, 0.24 mmol) to afford 94 mg (78% yield) of compound MM-I-83 as awhite solid: ¹H NMR (400 MHz, CD₃OD) δ 7.56 (bs, 1H), 7.35 (d, J=8.85Hz, 1H), 7.29 (dd, J=8.72, 5.27 Hz, 1H), 7.25 (m, 1H), 7.15 (t, J=7.84Hz, 1H), 7.03-6.09 (m, 2H), 6.95 (s, 1H), 6.74 (dt, J=9.59, 2.30 Hz,1H), 6.59 (bs, 1H), 4.24 (s, 2H), 4.06 (s, 2H), 3.66-3.62 (m, 2H), 2.31(t, J=7.04 Hz, 2H), 1.38 (quint., J=7.13 Hz, 1H). ¹³C NMR (100 MHz,CD₃OD) δ 159.95 (d, J_(C,F)=235.84 Hz), 154.70, 153.71, 138.04, 136.82(d, J_(C,F)=12.54 Hz), 134.80, 131.71, 131.07, 130.34, 130.08, 126.97,123.53 (d, J_(C,F)=2.91 Hz), 123.38, 122.44, 118.87, 118.77, 108.20,107.39 (d, J_(C,F)=24.81 Hz), 97.06 (d, J_(C,F)=25.93 Hz), 42.75, 29.80,28.79, 23.37, 21.52. LCMS (15-95% acetonitrile in 0.05% TFA over 10minutes) retention time=6.18 minutes, ESI m/z=493, 495 [M+H]⁺.

Synthesis of tert-butyl2-(2-(3-(trifluoromethoxy)phenyl)acetyl)hydrazine carboxylate (28n)

Prepared according to General Procedure 1A from2-(2-trifluoromethoxyphenyl)acetic acid (27n) (3.00 g, 18.05 mmol) andtert-butyl hydrazinecarboxylate (2.98 g, 22.6 mmol) to afford 4.62 g(91% yield) of compound 28n as yellow solid: ¹H NMR (400 MHz, CDCl₃) δ7.71 (bd, J=2.62 Hz, 1H), 7.29-7.24 (m, 3H), 6.95-6.89 (m, 2H), 6.43(bs, 1H), 3.86 (s, 3H), 3.60 (s, 2H), 1.41 (bs, 9H). ¹³C NMR (100 MHz,CDCl₃) δ 170.53, 157.09, 155.30, 131.35, 129.14, 122.50, 121.27, 110.86,81.74, 55.69, 36.74, 28.16. LCMS (50-95% acetonitrile in 0.05% TFA over10 minutes) retention time=3.07 min, ESI m/z=281, [M+H]⁺.

Synthesis of tert-butyl 2-(2-(3-nitrophenyl)acetyl)hydrazinecarboxylate(28o)

Prepared according to General Procedure 1A from 2-(3-nitrophenyl)aceticacid (27o) (3.00 g, 16.6 mmol) and tert-butyl hydrazinecarboxylate (2.74g, 20.7 mmol) to afford 2.32 g (47% yield) of compound 28o as yellowsolid: ¹H NMR (400 MHz, CD₃OD) δ 8.18-8.23 (m, 1H), 8.07-8.14 (m, 1H),7.71 (d, J=7.84 Hz, 1H), 7.54 (t, J=7.93 Hz, 1H), 3.66 (bs, 2H), 1.44(s, 9H). ¹³C NMR (100 MHz, CD₃OD) δ 171.04, 156.39, 148.35, 137.09,135.46, 129.30, 123.89, 121.61, 80.58, 39.34, 27.16. LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=3.00 min, ESIm/z=196, [M-Boc]⁺.

Synthesis of tert-butyl2-(2-(3-(benzyloxy)phenyl)acetyl)hydrazinecarboxylate (28p)

Prepared according to General Procedure 1A from2-(3-(benzyloxy)phenyl)acetic acid (27p) (3.00 g, 12.4 mmol) andtert-butyl hydrazinecarboxylate (2.05 g, 15.5 mmol) to afford 4.06 g(92% yield) of compound 28p as yellow solid: ¹H NMR (400 MHz, CD₃OD) δ7.44-7.36 (m, 2H), 7.35-7.25 (complex m, 3H), 7.18 (t, J=7.93 Hz, 1H),6.99 (bs, 1H), 6.90-6.80 (m, 2H), 5.04 (s, 2H), 3.48 (bs, 2H), 1.44 (bs,9H). ¹³C NMR (100 MHz, CD₃OD) δ 172.15, 159.05, 156.39 137.40, 136.31,129.17, 128.13, 127.50, 127.26, 121.46, 115.34, 113.22, 80.47, 69.56,40.20, 27.19. LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=5.32 min, ESI m/z=357, [M+H]⁺.

Synthesis of tert-butyl 2-(2-(3-cyanophenyl)acetyl)hydrazinecarboxylate(28q)

Prepared according to General Procedure 1A from 2-(3-cyanophenyl)aceticacid (27q) (4.95 g, 30.7 mmol) and tert-butyl hydrazinecarboxylate (5.07g, 38.4 mmol) to afford 4.42 g (52% yield) of compound 28q as yellowsolid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (bs, 1H), 8.77 (bs, 1H),7.69-7.67 (m, 1H), 7.67 (s, 1H), 7.57 (d, J=7.62 Hz, 1H), 7.49 (t,J=7.94 Hz, 1H), 3.48 (bs, 2H), 1.35 (bs, 9H). ¹³C NMR (100 MHz, DMSO-d₆)δ 169.53, 155.76, 137.80, 134.69, 133.11, 130.94, 130.03, 119.29,111.68, 79.72, 28.55. LCMS (25-95% acetonitrile in 0.05% TFA over 10minutes) retention time=5.70 min, ESI m/z=276, [M+H]⁺.

Synthesis of tert-butyl 2-(2-(4-fluorophenynacetyl)hydrazinecarboxylate(28r)

Prepared according to General Procedure 1A from 2-(4-fluorophenyl)aceticacid (2.00 g, 12.9 mmol) and tert-butyl hydrazinecarboxylate (2.13 g,16.1 mmol) to afford 3.34 g of compound 28r (97% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.71 (s, 1H), 7.26 (dd,³J_(HF)=8.20, J_(HH)=5.50 Hz, 2H), 7.08 (apparent t, ³J_(HF)=9.10,J_(HH)=9.10 Hz, 2H), 3.36 (s, 2H), 1.35 (s, 9H). ¹³C NMR (100 MHz,DMSO-d₆) δ 170.08, 161.61 (d, ¹J_(CF)=241 Hz), 155.78, 132.34 (d,⁴J_(CF)=2.80 Hz), 131.4 (d, ³J_(CF)=7.60 Hz), 115.4 (d, ²J_(CF) 21.1Hz), 79.62, 28.56. LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=3.08 minutes, ESI m/z=269, [M+H]⁺.

Synthesis of 2-(3-(trifluoromethoxy)phenyl)acetic hydrazide (29n)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3-(trifluoromethoxy)phenyl)acetyl)hydrazinecarboxylate (28n) (3.76g, 11.2 mmol) to afford 2.54 g (83% yield) of the intermediate HCI saltas a white solid. The HCI salt (2.54 g, 9.37 mmol) was then converted to1.88 g (71% yield) of freebase 29n (69% for two steps), isolated as awhite solid: ¹H NMR (400 MHz, CDCl₃) δ 7.36 (t, J=5.86 Hz, 1H), 7.19(bd, J=7.73 Hz, 1H), 7.16-7.11 (m, 2H), 5.54 (s, 2H). ¹³C NMR (100 MHz,CDCl₃) δ 170.86, 149.62, 136.22, 130.37, 127.77, 121.93, 120.47 (q,J_(C,F)=257.48 Hz), 119.96, 41.39. LCMS (15-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=6.17 minutes, ESI m/z=235, [M+H]⁺;276, [M+H+ACN]⁺.

Synthesis of 2-(3-nitrophenyl)acetic hydrazide (29o)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3-nitrophenyl)acetyl)hydrazinecarboxylate (280) (2.27 g, 7.69mmol) to afford 1.66 g (93% yield) of the intermediate HCI salt as awhite solid. The HCI salt (1.66 g, 7.17 mmol) was then converted to 1.31g (94% yield) of freebase 29o (87% for two steps), isolated as a lightyellow solid: ¹H NMR (400 MHz, CD₃OD) δ 8.19-8.17 (m, 1H), 8.12-8.10 (m,1H), 7.68 (d, J=7.10 Hz, 1H), 7.54 (t, J=8.01 Hz, 1H), 3.59 (s, 2H). ¹³CNMR (100 MHz, CD₃OD) δ 170.57, 148.35, 137.60, 135.24, 129.33, 123.59,121.56, 39.65. LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=2.05 minutes, ESI m/z=196, [M+H]⁺; 237, [M+H+ACN]⁺.

Synthesis of 2-(3-(benzyloxy)phenyl)acetic hydrazide (29p)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3-(benzyloxy)phenyl)acetyl)hydrazinecarboxylate (28p) (4.02 g,11.3 mmol) to afford 2.65 g (81% yield) of the intermediate HCI salt asa white solid. The HCI salt (2.65 g, 9.07 mmol) was then converted to2.00 g (86% yield) of freebase 29p (70% for two steps), isolated as awhite solid: ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.25 (complex m, 5H), 7.18(t, J=8.00 Hz, 1H), 6.93 (apparent t, J=1.90 Hz, 1H), 6.85 (dd, J=8.10,2.06 Hz, 2H), 5.04 (s, 2H), 3.40 (s, 2H). ¹³C NMR (100 MHz, CD₃OD) δ171.69, 159.05, 137.37, 136.73, 129.21, 128.14, 127.51, 127.25, 121.27,115.37, 113, 69.54, 40.45. LCMS (25-95% acetonitrile in 0.05% TFA over10 minutes) retention time=5.43 minutes (broad), ESI m/z=257, [M+H]⁺;535, [2M+Na]⁺.

Synthesis of 2-(3-cyanophenyl)acetic hydrazide (29 g)

Prepared according to the General Procedure 1B from tert-butyl2-(2-(3-cyanophenyl)acetyl)hydrazinecarboxylate (28q) (4.32 g, 15.7mmol) to afford 2.60 g (79% yield) of the intermediate HCI salt as awhite solid. The HCI salt (2.60 g, 12.3 mmol) was then converted to 1.41g (75% yield) of freebase 29q (59% for two steps), isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (bs, 1H), 7.68-7.65 (m, 2H),7.57-7.54 (m, 1H), 7.47 (t, J=7.79 Hz, 1H), 4.21 (bs, 2H), 3.39 (s, 2H).¹³C NMR (100 MHz, DMSO-d₆) δ 169.29, 138.41, 134.59, 132.98, 130.82,129.98, 119.32, 111.64, benzyl carbon obscured by DMSO-d₆ solvent peaks.LCMS (25-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=2.07 minutes, ESI m/z=176, [M+H]⁺.

Synthesis of 2-(4-fluorophenyl)acetic hydrazide (29r)

Produced according to General Procedure B from tert-butyl2-(2-(4-fluorophenyl)acetyl)hydrazinecarboxylate 28r (3.23 g, 12.0 mmol)to afford 2.18 g of the intermediate HCI salt (89% yield) as a whitesolid. The HCI salt was converted to freebase afford 1.57 g of compound29r (90% yield) (78% yield over two steps) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 9.15 (s, 1H), 7.24 (dd, ⁴J_(HF)=8.80, J_(HH)=5.50 Hz,2H), 7.07 (apparent t, ³J_(HF)=8.70, J_(HH)=8.70 Hz, 2H), 4.17 (s, 2H).¹³C NMR (100 MHz, DMSO-d₆) δ 169.95, 161.54 (d, ¹J_(CF)=243 Hz), 132.96,131.25 (d, ³J_(CF)=7.60 Hz), 115.39 (d, 2J_(CF)=21.1 Hz), 40.73(partially obscured by DMSO solvent peak). LCMS (50-95% acetonitrile in0.05% TFA over 10 minutes) retention time=1.85 minutes, ESI m/z=169,[M+H]⁺.

Synthesis of3-(2-(5-(3-(trifluoromethoxy)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole (310)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (325 mg, 0.59 mmol) and 2-(3-(trifluoromethoxy)phenyl)acetichydrazide (29n) (165.8 mg, 0.71 mmol). Purification by flashchromatography (SiO₂, 30:1 CH₂Cl₂/methanol) afforded 203 mg (47% yield)of compound 31o as a tan solid: ¹H NMR (400 MHz, CD₃OD) δ 7.98 (dd,J=8.51, 1.45 Hz, 1H), 7.41 (t, J=7.85 Hz, 1H), 7.33-7.30 (m, 9H), 7.28(t, J=7.85 Hz, 1H), 7.18 (d, J=8.16 Hz, 1H), 7.05-7.02 (m, 8H),6.98-6.93 (m, 2H), 6.89 (s, 1H), 6.84 (t, J=7.65 Hz, 1H), 6.44 (bs, 1H),4.07 (s, 2H), 3.38-3.34 (m, 2H), 3.17 (t, J=7.03 Hz, 2H), 3.00 (t,J=7.06 Hz, 2H), 2.19 (t, J=7.09 Hz, 1H), 1.36-1.32 (m, 4H). ¹³C NMR (100MHz, CD₃OD) δ 155.97, 152.63, 149.38, 142.24, 138.98, 138.28, 138.14,136.67, 130.29, 129.44, 129.26, 127.99, 127.92, 126.97, 126.90, 122.13,121.10, 120.88, 120.46 (q, J_(C,F)=255.77 Hz), 119.41, 118.45, 117.71,112.95, 111.05, 75.42, 42.26, 29.85, 28.63, 25.79, 24.13, 23.57. LCMS(50-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=5.25minutes, ESI m/z=737, [M+H]⁺.

Synthesis of3-(2-(5-(3-nitrobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl))-1H-indole(31p)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (500 mg, 0.90 mmol) and 2-(3-nitrophenyl)acetic hydrazide (290)(211 mg, 1.08 mmol). Purification by flash chromatography (SiO₂, 40:1CH₂Cl₂/methanol to 10/1) afforded 328 mg (52% yield) of compound 31p asa tan solid: ¹H NMR (400 MHz, CD₃OD) δ 8.02-7.97 (m, 1H), 8.00 (s, 1H),7.47-7.42 (m, 1H), 7.40-7.35 (m, 1H), 7.34-7.28 (m, 11H), 7.15 (d,J=8.20 Hz, 1H), 7.05-7.01 (m, 6H), 6.92 (t, J=7.63 Hz, 1H), 6.89 (s,1H), 6.83 (t, J=7.70 Hz, 1H), 6.43 (s, 1H), 4.13 (s, 2H), 3.35-3.31 (m,2H), 3.17 (t, J=7.14 Hz, 2H), 3.02 (t, J=6.92 Hz, 2H), 2.21 (t, J=7.01Hz, 2H), 1.38 (quint., J=7.17 Hz, 2H). ¹³C NMR (100 MHz, CD₃OD) &156.06, 152.36, 148.46, 142.23, 138.90, 138.20, 137.86, 136.65, 134.45,132.34, 129.79, 129.44, 129.31, 128.00, 127.93, 126.99, 123.10, 122.20,121.88, 121.10, 118.46, 117.68, 112.91, 111.07, 75.42, 42.23, 29.74,28.61, 25.79, 24.08, 23.68. LCMS (50-95% acetonitrile in 0.05% TFA over10 minutes) retention time=3.87 minutes, ESI m/z=698, [M+H]⁺.

Synthesis of3-(2-(5-(3-(benzyloxy)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31q)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (500 mg, 0.90 mmol) and 2-(3-(benzyloxy)phenyl)acetic hydrazide(29p) (277 mg, 1.08 mmol). Purification by flash chromatography (SiO₂,30:1 CH₂Cl₂/methanol to 20/1) afforded 335 mg (49% yield) of compound31q as a white foam: ¹H NMR (400 MHz, CD₃OD) δ 7.35-7.26 (m, 11H),7.25-7.23 (m, 4H), 7.18 (d, J=8.12 Hz, 1H), 7.13-7.10 (m, 1H), 7.04-7.00(m, 7H), 6.95 (t, J=7.01 Hz, 1H), 6.89 (s, 1H), 6.88 (t, J=7.31 Hz, 1H),6.68-6.64 (m, 2H), 6.55 (d, J=7.61 Hz, 1H), 6.36 (s, 1H), 5.65 (s, 2H),4.90 (s, 2H), 3.98 (bs, 2H), 3.16 (t, J=7.24, 2H), 2.97 (t, J=7.15 Hz,2H), 2.10 (t, J=7.23 Hz, 2H), 1.15 (quint., J=7.45 Hz, 2H). ¹³C NMR (100MHz, CD₃OD) δ 159.08, 155.83, 153.17, 142.24, 139.07, 138.05, 137.09,137.01, 136.67, 129.70, 129.47, 128.18, 127.99, 127.94, 127.49, 127.18,126.99, 122.12, 121.10, 120.43, 118.46, 118.41, 117.71, 114.52, 113.66,112.98, 111.04, 75.41, 69.40, 42.33, 30.35, 28.45, 25.76, 24.29, 23.52.LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=5.50 minutes, ESI m/z=759, [M+H]⁺.

Synthesis of3-((5-(2-(1H-indol-3-yl)ethyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)benzonitrile(31r)

Prepared according to the General Procedure 1C from3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanethioamide(10) (500 mg, 0.90 mmol) and 2-(3-cyanophenyl)acetic hydrazide (29q)(189 mg, 1.08 mmol). Purification by flash chromatography (SiO₂, 40:1CH₂Cl₂/methanol to 20/1) afforded 330 mg (54% yield) of compound 31r asa white foam: ¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (bs, 1H), 7.90 (dd,J=8.34, 1.46 Hz, 1H), 7.64 (s, 1H), 7.60 (dt, J=7.23, 1.65 Hz, 1H),7.48-7.45 (m, 1H), 7.43 (d, J=7.50 Hz, 1H), 7.39 (d, J=7.32 Hz, 1H),7.35-7.29 (m, 9H), 7.26 (d, J=8.15 Hz, 1H), 7.20 (d, J=0.93 Hz, 1H),7.08 (d, J=2.19 Hz, 1H), 7.01-6.95 (m, 6H), 6.83 (t, J=7.26 Hz, 1H),6.50 (s, 1H), 4.08 (s, 2H), 3.71 (apparent t, J=7.89 Hz, 2H), 3.05(apparent t, J=7.09 Hz, 2H), 2.92 (dd, J=8.63, 6.70 Hz, 2H), 2.32 (t,J=7.02 Hz, 2H), 1.56 (quint., J=7.52 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆)δ 154.70, 152.34, 142.81, 140.13, 138.96, 138.31, 136.68, 134.20,133.39, 132.73, 130.99, 130.18, 129.78, 129.65, 129.10, 128.70, 128.46,127.43, 123.10, 121.41, 119.20, 118.72, 118.67, 118.10, 113.85, 111.85,74.85, 42.49, 30.10, 29.64, 25.90, 25.00, 23.20. LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=3.58 minutes,ESI m/z=678, [M+H]⁺.

Synthesis of3-(2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(3-(trifluoromethoxy)benzyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(MM-I-36)

Prepared according to the General Procedure 1D from3-(2-(5-(3-(trifluoromethoxy)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-ypethyl)-1H-indole(31o) (172 mg, 0.23 mmol) to afford 82 mg (71% yield) of MM-I-36 as awhite solid: ¹H NMR (400 MHz, CD₃OD) δ 7.52 (s, 1H), 7.34 (t, J=7.97 Hz,1H), 7.27 (t, J=7.74 Hz, 2H), 7.10 (bd, J=8.24 Hz, 1H), 7.03 (t, J=7.85Hz, 1H), 7.02 (bd, J=1.54 Hz, 1H), 6.92 (d, J=7.65 Hz, 2H), 6.89-6.87(m, 1H), 6.57 (s, 1H), 4.04 (s, 2H), 3.34-3.30 (m, obscured by NMRsolvent, 2H), 3.16 (t, J=7.13 Hz, 2H), 3.01 (t, J=7.14 Hz, 2H), 2.26 (t,J=7.03 Hz, 2H), 1.43 (quint., J=7.12 Hz, 2H). ¹³C NMR (100 MHz, CD₃OD) δ156.07, 152.61, 149.39, 138.16, 136.67, 134.81, 130.30, 126.97, 126.86,122.13, 121.10, 120.83, 120.51 (q, J_(C,F)=255.66 Hz), 119.36, 118.47,117.62, 112.91, 111.00, 42.10, 29.85, 28.77, 25.81, 23.65, 23.12. LCMS(15-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=2.15minutes, ESI m/z=495, [M+H]⁺, 989 [2M+H]⁺.

Synthesis of3-(2-(4-(3-1H-Imidazol-4-yl)propyl)-5-(3-nitrobenzyl)-4H-1,2,4-triazol-3-yl)ethyl))-1H-indole(MM-I-43)

Prepared according to General Procedure 1D from3-(2-(5-(3-nitrobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31p) (0.148 g, 0.212 mmol) to afford 0.085 g (88% yield) of MM-I-43 asa white solid: ¹H NMR (400 MHz, CD₃OD) imidazole tautomers observed: δ8.05-8.12 (m, 1H), 7.97 (bs, 1H), 7.44-7.55 (m, 2H), 7.21-7.37 (m, 4H),6.98-7.05 (m, 1H), 6.85-6.95 (m, 2H), 6.57 (bs, 1H), 4.10 (s, 2H), 3.31(obs s, 1H), 3.17 (apparent t, J=6.9, 2H), 3.03 (apparent t, J=8.08,2H), 2.28 (apparent t, J=7.1, 2H), 1.46 (quint., J=7.71, 2H). ¹³C NMR(100 MHz, CD₃OD) imidazole tautomers observed: δ 156.14, 152.36, 148.50,137.75, 136.66, 134.88, 134.42, 129.80, 126.98, 123.04, 122.19, 121.80,121.09, 118.47, 117.59, 112.89, 111.00, 42.07, 32.42, 29.75, 28.80,25.84, 23.74. LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=3.87 min, ESI m/z=699, [M+H]⁺.

Synthesis of3-(2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(3-(benzyloxy)benzyl)-4H-1,2,4-triazol-3-yl)-ethyl)-1H-indole(MM-I-53)

Prepared according to general procedure 1D from3-(2-(5-(3-(benzyloxy)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(31q) (148 mg, 0.21 mmol) to afford 85.0 mg (88% yield) of MM-I-53 as awhite solid: ¹H NMR (400 MHz, CD₃OD), significant broadening observed atroom temperature: δ 7.52 (bs, 1H), 7.34-7.22 (m, 5H), 7.14 (t, J=7.90Hz, 1H), 7.03 (t, J=7.28 Hz, 1H), 6.92 (t, J=7.45 Hz, 1H), 6.87 (s, 1H),6.82 (dd, J=8.13, 1.31 Hz, 1H), 6.67 (s, 1H), 6.54 (d, J=7.41 Hz, 1H),4.99 (s, 2H), 3.96 (s, 2H), 3.29-3.25 (m, obscured by NMR solvent, 2H),3.16 (bt, J=6.87 Hz, 2H), 2.98 (bt, J=6.67 Hz, 2H), 2.22-2.15 (bm, 2H),1.34-1.25 (bm, 2H). ¹³C NMR (100 MHz, CD₃OD): δ 159.15, 137.19, 136.88,136.67, 129.71, 128.18, 127.52, 127.22, 126.98, 122.11, 121.10, 120.47,118.48, 117.64, 114.58, 113.52, 112.93, 111.00, 69.45, 42.23, 30.37,28.63, 25.80, 23.57, 23.25 (broad). LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=2.20 min, ESI m/z=517, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-3-yl)methyl)benzonitrile(MM-I-63)

Prepared according to general procedure 1D from 3-((5-(2-(1H-indol-3-yl)ethyl)-4-(3-(1-trityl-1H-imidazol-4-yl) propyl)-4H-1,2,4-triazol-3-yl)methyl)benzonitrile (31r) (292 mg, 0.43 mmol) to afford 135 mg (72%yield) of MM-I-63 as a white solid: ¹H NMR (400 MHz, DMSO-d₆): δ 11.74(bs, 1H), 10.77 (s, 1H), 7.68 (dt, J=6.91, 1.58 Hz, 1H), 7.64 (s, 1H),7.50-7.44 (m, 3H), 7.40 (d, J=7.85 Hz, 1H), 7.28 (d, J=8.11 Hz, 1H),7.11 (d, J=2.17 Hz, 1H), 7.01 (dt, J=7.01, 0.76 Hz, 1H), 6.91 (t, J=7.26Hz, 1H), 6.70 (bs, 1H), 4.10 (bs, 2H), 3.72 (bt, J=6.70 Hz, 2H), 3.07(dd, J=8.50, 5.42 Hz, 2H), 2.93 (dd, J=8.66, 5.49 Hz, 2H), 2.36 (bt,J=6.23 Hz, 2H), 1.63 (quint., J=7.29 Hz, 2H). ¹³C NMR (100 MHz,DMSO-d₆): δ 154.74, 152.36, 138.92, 136.68, 135.22, 134.20, 132.71,131.08, 130.25, 127.45, 123.13, 121.44, 119.25, 118.80, 118.69, 113.88,111.88, 42.49, 30.18, 29.87 (2 broadened carbons), 25.92, 23.22. LCMS(50-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=1.70min, ESI m/z=436, [M+H]⁺.

Synthesis of2-(5-methoxy-1H-indol-3yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)-acetamide(B)

To a solution of 2-(5-methoxy-1H-indol-3-yl)acetic acid (A) (2.00 g,4.87 mmol) in DMF (40 mL) was added EDC.HCl (1.40 g, 7.31 mmol) andHOBt.H₂O (933 mg, 6.09 mmol). The resulting mixture was stirred at RTfor 45 min and treated with compound 7 (1.79 g, 4.87 mmol). The “pH” ofthe solution was adjusted ˜9 by the addition of TEA (˜1.35 mL) and thereaction was stirred at RT for 16 hours. After this time water (200 mL)was added and the resulting precipitate was collected by filtration anddried by azeotropic distillation with toluene to afford 2.38 g (88%yield) of compound B as a white solid: ¹H NMR (400 MHz, DMSO-d₆): δ10.64 (bs, 1H), 7.85 (t, J=5.50 Hz, 1H), 7.38-7.30 (m, 9H), 7.18 (s,1H), 7.15 (d, J=8.70 Hz, 1H), 7.07-6.98 (m, 8H), 6.63 (dd, J=8.60, 2.80Hz, 1H), 6.52 (s, 1H), 3.63 (s, 3H), 3.38 (s, 2H), 3.00 (q J=6.00 Hz,2H), 2.36 (t, J=7.30 Hz, 2H), 1.59 (quint. J=7.30 Hz, 2H). ¹³C NMR (100MHz, DMSO-d₆): δ 171.01, 153.46, 142.90, 141.17, 138.14. 131.75, 129.71,128.70, 128.45, 128.00, 124.91, 118.02, 112.44, 111.59, 109.29, 100.96,74.83, 55.75, 38.76, 33.42, 29.53, 25.83. LCMS (50-95% acetonitrile in0.05% TFA over 10 minutes) retention time=3.87 min, ESI m/z=555, [M+H]⁺.

Synthesis of2-(5-methoxy-1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propylethane-thioamideC)

A solution of2-(5-methoxy-1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)acetamide(B) (azeotropically dried by coevaporation with toluene, 2.00 g, 3.61mmol) and Lawesson's reagent (946 mg, 2.34 mmol) in THF (35 mL) washeated to 70° C. for 3 hours. The resulting mixture was allowed to coolto room temperature and concentrated. Purification by flash columnchromatography (SiO₂, 40:1 to 20:1 CH₂Cl₂/MeOH) afforded 1.82 g (88%yield) of compound C as a yellow foam: ¹H NMR (400 MHz, DMSO-d₆) δ 10.69(bs, 1H), 9.94 (bt, J˜5.0 Hz, 1H), 7.38-7.30 (m, 9H), 7.15 (d, J=9.10Hz, 1H), 7.13 (d, J=2.30 Hz, 1H), 7.07-7.03 (m, 8H), 6.64 (d, J=2.30 Hz,1H), 6.61 (bs, 1H), 3.91 (s, 2H), 3.63 (s, 3H), 3.44 (q, J=6.80 Hz, 2H),2.40 (t, J=7.40 Hz, 2H), 1.76 (quint., J=7.30 Hz, 2H). ¹³C NMR (100 MHz,DMSO-d₆): δ 202.13, 153.50, 142.65, 138.07, 131.71, 129.71, 128.76,128.53, 127.76, 125.20, 118.39, 112.50, 111.57, 110.33, 101.15, 75.19,55.78, 45.49, 42.94, 27.43, 25.44. LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=5.32 min, ESI m/z=571, [M+H]⁺.

Synthesis of2-(1H-indol-3-yl)-N-(3-(1-trityl-H-imidazol-4-yl)propyl)acetamide (F)

To a solution of 2-(1H-indol-3-yl)acetic acid (E) (816 mg, 4.66 mmol) inDMF (50 mL) was added EDC.HCl (1.34 g, 6.99 mmol) and HOBt.H₂O (892 mg,5.83 mmol). The resulting mixture was stirred at room temperature for 45min. A solution of the amine 7 (1.71 g, 4.66 mmol) in DMF (50 mL) andTEA (1.70 mL) were added and the reaction was stirred for 16 hours atroom temperature. The mixture was poured into water (150 mL) in a largebeaker and stirred for 30 minutes at room temperature. The solid wascollected by filtration. Trituration of the solid with hot ACN andfiltration afforded 1.10 g (45% yield) of pure amide F: ¹H NMR (400 MHz,DMSO-d₆) δ 10.80 (bs, 1H), 7.84 (t, J=5.38 Hz, 1H), 7.47 (d, J=7.88 Hz,1H), 7.38-7.38 (m, 8H), 7.27 (d, J=8.13 Hz, 2H), 7.18 (d, =1.03 Hz, 1H),7.11 (d, J=2.03 Hz, 1H), 7.04-7.02 (m, 6H), 6.97 (t, J=7.23 Hz, 1H),6.84 (t, J=7.21 Hz, 1H), 6.52 (s, 1H), 3.42 (s, 2H), 2.98 (apparent q,J=6.59 Hz, 2H), 2.34 (t, J=7.42 Hz, 2H), 1.59 (quint., J=7.06 Hz, 2H).LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=4.33 min, ESI m/z=525, [M+H]⁺.

Synthesis of2-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)ethanethioamide(G)

A mixture of 3-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)propanamide (F) (1.01 g, 1.90 mmol; previously dried by 3 azeotropiccoevaporations with toluene, 30 mL each) and Lawesson's reagent (499.5mg, 1.24 mmol) in THE (45 mL) was heated to 65° C. for 3.5 hours. Afterthis time, the reaction was cooled and concentrated. The residue waspurified by flash column chromatography (SiO2, 30/1 CH₂Cl₂/MeOH) toafford 314 mg (31% yield) of thioamide G as a tan foam: ¹H NMR (400 MHz,DMSO-d₆) δ 10.84 (bs, 1H), 9.90 (t, J=5.03 Hz, 1H), 7.53 (d, J=7.80 Hz,1H), 7.38-7.28 (m, 10H), 7.26 (d, J=7.99 Hz, 1H), 7.16 (d, J=2.31 Hz,1H), 7.05-7.02 (m, 6H), 6.97 (dt, J=7.02, 0.58 Hz, 1H), 6.84 (dt,J=7.89, 0.80 Hz, 1H), 6.57 (bs, 1H), 3.95 (s, 2H), 3.45-3.39 (m, 2H),2.38 (t, J=7.33 Hz, 2H), 1.75 (quint., J=7.31, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 202.11, 142.75, 140.40, 138.10, 136.59, 129.72, 128.74,128.50, 127.45, 124.53, 121.43, 119.27, 118.82, 118.32, 111.86, 110.61,75.04, 45.50, 42.84, 27.40, 25.57. LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=5.42 min, ESI m/z=541, [M+H]⁺.

Synthesis of2-(6-fluoro-1H-indol-3-yl)-N-(3-(1-trityl-H-imidazol-4-yl)propyl)acetamide (I)

To a solution of 2-(6-fluoro-1H-indol-3-yl)acetic acid (H) (1.00 g, 5.18mmol) in DMF (50 mL) was added EDC.HCl (1.50 g, 7.77 mmol) and HOBt.H₂O(1.19 g, 7.77 mmol). The resulting mixture was stirred at roomtemperature for 1 h. A solution of the amine 7 (1.90 g, 5.18 mmol) andTEA (2.80 mL) were added and the reaction was stirred for 16 hours atroom temperature. The mixture was partitioned with EtOAc (120 mL) and 1NNaHSO₄ (100 mL). The layers were separated and the EtOAc solution waswashed with water (150 mL), sat. NaHCO₃ (150 mL) and brine (150 mL). TheEtOAc layer was dried (Na₂SO₄), filtered and concentrated. Triturationof the solid with hot ACN and filtration afforded 1.58 g (56% yield) ofpure amide I. ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (bs, 1H), 7.89 (t,J=5.48 Hz, 1H), 7.45 (dd, J=8.69, 5.53 Hz, 1H), 7.37-7.23 (complex m,9H), 7.19 (d, J=1.20 Hz, 1H), 7.11 (d, J=2.36 Hz, 1H), 7.06-7.01 (m,7H), 6.73 (ddd, J=11.04, 9.73, 2.33 Hz, 1H), 6.53 (bs, 1H), 3.40 (s,2H), 2.98 (apparent q, J=6.71 Hz, 2H), 2.35 (t, J=7.44 Hz, 2H), 1.58(quint., J=7.19 Hz, 2H). LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=4.38 min, ESI m/z=543, [M+H]⁺.

Synthesis of 2-(6-fluoro-1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4yl)propyl)ethane-thioamide (J)

A mixture of2-(6-fluoro-1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)-acetamide(I) (1.58 g, 2.91 mmol; previously dried by 3 azeotropic coevaporationswith toluene, 30 mL each) and Lawesson's reagent (789 mg, 1.95 mmol) inTHE (75 mL) was heated to 65° C. for 2.5 hours. After this time, thereaction was cooled and concentrated. The residue was purified by flashcolumn chromatography (SiO₂, 40/1 CH₂Cl₂/MeOH to 20/1) to afford 1.18 g(73% yield) of thioamide J as a tan foam: ¹H NMR (400 MHz, DMSO-d₆) δ10.88 (bs, 1H), 9.90 (t, J=4.95 Hz, 1H), 7.52 (dd, J=8.70, 5.53 Hz, 1H),7.39-7.31 (complex m, 9H), 7.16 (d, J=2.30 Hz, 1H), 7.08-7.03 (m, J=7H),6.73 73 (ddd, J=11.05, 8.80, 2.32 Hz, 1H), 3.93 (s, 2H), 3.42 (apparentq, J=6.65 Hz, 2H), 2.42 (t, J=7.43 Hz, 2H), 1.76 (quint., J=7.36 Hz,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 201.98, 159.30 (d, J_(C,F)=234.1 Hz),142.56, 139.73, 137.99, 136.44 (d, J_(C,F)=12.7 Hz), 129.72, 128.78,128.57, 125.11, 124.36, 120. 30 (d, J_(C,F)=10.3 Hz), 118.53, 110.95,107.29 (d, J_(C,F)=24.3 Hz), 97.80 (d, J_(C,F)=25.7 Hz), 75.40, 45.44,42.72, 27.26, 25.22. LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=5.83 min, ESI m/z=559, [M+H]⁺.

Synthesis of3,3-dimethyl-N-(3-(1-trityl-1H-imidazol-4-yl)Propyl)butanamide (L)

To a solution of 3,3-dimethylbutanoic acid K (1.00 g, 8.61 mmol) in DMF(50 MI) was added EDC.HCl (2.48 g, 12.9 mmol) and HOBt.H₂O (1.65 g, 10.8mmol) and the resulting mixture was stirred for 30 minutes at roomtemperature. After this time, a solution of amine 7 (3.00 g, 8.61 mmol),and TEA (1.74 g, 2.40 mL, 17.2 mmol) in DMF (20 mL) was added and thereaction was stirred for 16 hours thereafter. Workup as described in theprevious examples afforded 3.10 g of compound L (77% yield) as a white:¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (t, J=5.10 Hz, 1H), 7.35 (m, 9H), 7.20(apparent d, J=1.40 Hz, 1H), 7.04 (dd, J=8.90, J=2.60 Hz, 6H), 6.56(apparent d, J=1.40 Hz, 1H), 2.96 (q, J=6.90 Hz, 2H), 2.37 (t, J=7.40Hz, 2H), 1.87 (s, 2H), 1.58 (quint., J=7.30 Hz, 2H), 0.88 (s, 9H). ¹³CNMR (100 MHz, DMSO-d₆) δ 171.07, 142.90, 141.15, 138.17, 129.71, 128.70,128.46, 118.09, 74.84, 49.38, 38.37, 30.88, 30.21, 29.45, 25.81. LCMS(50-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=4.93minutes, ESI m/z=466, [M+H]⁺

Synthesis of3,3-dimethyl-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)butanethioamide (M)

Produced following General Procedure D from amide L (2.95 g, 6.34 mmol)and Lawesson's reagent (1.67 g, 4.12 mmol), which afforded ˜5.5 g crudematerial as a brown oil after 7 hours of reflux (reaction determined tobe mostly complete by LCMS). The crude was purified by flashchromatography (SiO₂, 80:1 CH₂Cl₂:MeOH to 40:1) which afforded 1.32 g ofM as a tan foam (43% purified yield): LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=6.13 minutes, ESI m/z=482, [M+H]⁺.

Synthesis of3-((5-(4-methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(70)

Prepared according to the General Procedure 1C from2-(1H-indol-3-yl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)ethanethioamideG (500 mg, 0.93 mmol), 2-(4-methoxyphenyl)acetic hydrazide (208 mg, 1.16mmol), silver benzoate (424 mg, 1.85 mmol), and acetic acid (167 mg, 159μL, 2.78 mmol), which formed ˜1.4 g of crude material. The crude waspurified by flash chromatography (SiO₂, 40:1 CH₂Cl₂:MeOH to 30:1, to20:1) afforded 97 mg (16% yield) of compound 70 as a white solid: LCMS(50-95% acetonitrile in 0.05% TFA over 10 minutes) retention time=3.63minutes, ESI m/z=669, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(SK-I-23)

Prepared according to general procedure 1D from3-((5-(4-methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole70 (97 mg, 0.15 mmol) and afforded 48 mg (77% yield) of compound SK-I-23as a tan solid: LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=1.72 minutes, ESI m/z=427, [M+H]⁺.

Synthesis of3-((5-(4-fluorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-5-methoxy-1H-indole(72)

Prepared according to General Procedure 1C from thioamide C (300 mg,0.53 mmol), 2-(4-fluorophenyl)acetic hydrazide (111 mg, 0.66 mmol),silver benzoate (243 mg, 1.06 mmol), and acetic acid (95 mg, 90.9 μL,1.59 mmol), which afforded 735 mg of crude material. The crude waspurified by flash chromatography (SiO₂, 40:1 CH₂Cl₂:MeOH to 20:1) toafford 159 mg (43% yield) of compound 72: ¹H NMR (400 MHz, DMSO-d₆) δ10.70 (bs, 1H), 7.90 (d, J=8.20 Hz, 1H), 7.46 (t, J=8.10 Hz, 1H),7.36-7.29 (m, 9H), 7.21 (bs, 1H), 7.14-7.10 (m, 3H), 7.06 (d, J=1.80 Hz,1H), 7.00-6.98 (m, 6H), 6.91 (d, J=2.30 Hz, 1H), 6.62 (dd, J=8.30, 2.30Hz, 1H), 6.45 (bs, 1H), 4.08 (s, 2H), 3.97 (s, 2H), 3.68 (apparent t,J=7.80 Hz, 2H), 2.24 (t, J=7.60 Hz, 2H), 1.41 (quint., J=7.50 Hz, 2 h).¹³C NMR (100 MHz, DMSO-d₆) δ 161.47 (d, ¹J_(CF)=242 Hz), 160.26, 153.80,153.47, 153.19, 142.82, 140.17, 138.25, 133.39, 133.31 (d, 4J_(CF)=2.90Hz), 131.85, 130.83 (3J_(CF)=8.70 Hz), 129.78, 139.66, 129.10, 128.69,128.46, 127.63, 124.63 118.11, 115.64 (d, ²J_(CF)=22.0 Hz), 112.57,111.66, 109.02, 100.93, 74.87, 55.73, 42.70, 29.84, 29.44, 25.06, 21.87.LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=3.77 minutes, ESI m/z=687, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl)methyl)-5-methoxy-JH-indole(SK-I-55)

Prepared according to General Procedure 1D from3-((5-(4-fluorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-5-methoxy-1H-indole72 (144 mg, 0.21 mmol) and afforded 66 mg (71% yield) of compoundSK-I-55 as a tan residue. ¹H NMR (400 MHz, MeOH-d₄) δ 7.55 (s, 1H), 7.19(d, J=8.70 Hz, 1H), 7.05-7.02 (m, 2H), 7.97-7.92 (m, 3H), 6.83 (d,J=2.40 Hz, 1H), 6.72 (dd, J=8.70, 2.30 Hz, 1H), 6.55 (s, 1H), 4.24 (s,2H), 4.04 (s, 2H), 3.70 (s, 3H), 3.63-3.58 (m, 2H), 2.28 (t, J=6.80 Hz,2H), 1.38 (quint., J=6.80 Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄) δ 162.01(d, 1 J_(CF)=244 Hz), 154.87, 154.16, 153.92, 134.71, 131.99, 131.38 (d,⁴J_(CF)=2.90 Hz), 129.84 (d, ³J_(CF)=8.60 Hz), 126.97, 123.61, 115.22(d, ²J_(CF)=22.1 Hz), 111.89, 107.52, 99.54, 54.78, 42.75, 29.51, 28.69,23.33 (broad), 21.72. LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=5.92 minutes, ESI m/z=445, [M+H]⁺.

Synthesis of3-((5-benzyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-5-methoxy-1H-indole(74)

Prepared according to General Procedure 1C from thioamide C (300 mg,0.53 mmol), phenylacetic hydrazide (29n) (99 mg, 0.66 mmol), silverbenzoate (243 mg, 1.06 mmol), and acetic acid (95 mg, 90.9 μL, 1.59mmol), affording 738 mg of crude material. The crude was purified byflash chromatography (SiO₂, 40:1 CH₂Cl₂:MeOH to 20:1) to afford 118 mg(33% yield) of compound 74. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (bs 1H),7.90 (d, J=7.40 Hz, 1H), 7.46 (t, J=7.80 Hz, 1H), 7.36-7.32 (m, 9H),7.20 (s, 1H), 7.14-7.03 (complex m, 7H), 7.00-6.97 (m, 6H), 6.90 (d,J=2.30 Hz, 1H), 6.62 (dd, J=8.70, 2.30 Hz, 1H), 6.39 (s, 1H), 4.08 (s,2H), 3.98 (s, 2H), 3.68-3.64 (m, 2H), 2.22 (apparent t, J=6.90 Hz, 2H),1.36 (apparent quint., J˜7.00 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ153.79, 153.47, 153.24, 142.81, 140.17, 138.17, 137.19, 133.39, 131.85,129.78, 129.67, 129.09, 128.91, 128.87, 128.70, 128.47, 127.63, 127.01,124.62, 118.10, 112.57, 111.68, 109.02, 100.90, 74.88, 55.73, 42.73,30.71, 29.40, 25.11, 21.89. LCMS (50-95% acetonitrile in 0.05% TFA over10 minutes) retention time=3.43 minutes, ESI m/z=669, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-benzyl-4H-1,2,4-triazol-3-yl)methyl)-5-methoxy-1H-indole(SK-I-53)

Synthesized according to General Procedure 1D from3-((5-benzyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-5-methoxy-1H-indole74 (118 mg, 0.18 mmol) to afford 64 mg (85% yield) of compound SK-I-53as a tan solid. ¹H NMR (400 MHz, MeOH-d₄) δ 7.54 (s, 1H), 7.23-7.14(complex m, 4H), 7.02 (d, J=6.80 Hz, 2H), 6.92 (s, 1H), 6.84 (d, J=2.20Hz, 1H), 6.72 (dd, J=8.70 Hz, 2.70 Hz, 1H), 6.52 (s, 1H), 4.23 (s, 2H),4.06 (s, 2H), 3.70 (s, 3H), 3.61-3.57 (m, 2H), 2.25 (t, J=6.80 Hz, 2H),1.35 (quint., J=7.80 Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄) δ 154.82,154.27, 153.92, 135.43, 134.67, 131.98, 128.58, 127.99, 126.89, 123.58,111.91, 107.54, 99.51, 54.77, 42.77, 30.04, 28.61, 23.24 (broad), 21.73.LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=5.80 minutes, ESI m/z=427, [M+H]⁺.

Synthesis of5-methoxy-3-((5-(4-fluorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(76)

Created according to General Procedure 1C from thioamide C (311 mg, 0.54mmol), 2-(4-methoxyphenyl)acetic hydrazide (29d) (123 mg, 0.68 mmol),silver benzoate (247 mg, 1.08 mmol), and acetic acid (97 mg, 93 μL, 1.62mmol), which afforded 760 mg of crude material. The crude was purifiedby flash chromatography (SiO2, 40:1 CH₂CI₂/MeOH to 20:1) to afford 132mg (39% yield) of compound 76. ¹H NMR (400 MHz, DMSO-d₆) δ 10.7 (s, 1H),7.90 (d, J=6.80 Hz, 1H), 7.45 (t, J=7.80 Hz, 1H), 7.33 (m, 9H), 7.21 (s,1H), 7.11 (d, J=8.70 Hz, 1H), 7.04 (apparent d, J=1.80 Hz, 1H), 6.99 (m,6H), 6.90 (apparent d, J=2.30 Hz, 1H), 6.70 (d, J=8.70 Hz, 2H), 6.62(dd, J=8.70, J=2.30 Hz, 1H) 6.46 (s, 1H), 4.06 (s, 2H), 3.90 (s, 2H),3.64 (partially obs. t, J=7.30 Hz, 2H), 3.59 (s, 3H), 3.59 (s, 3H), 2.23(t, J=6.80 Hz, 2H), 1.41 (quint., J=6.80 Hz, 2H). LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=3.38 minutes,ESI m/z=699, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)methyl)-5-methoxy-1H-indole(SK-I-56)

Prepared according to General Procedure 1D from5-methoxy-3-((5-(4-methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(76) (112 mg, 0.16 mmol) and afforded 67 mg (92% yield) of compoundSK-I-56 as a light tan solid. ¹H NMR (400 MHz, MeOH-d₄) δ 7.54 (s, 1H),7.18 (d, J=8.70 Hz, 1H), 6.94-6.90 (m, 3H), 6.83 (d, J=2.70 Hz, 1H),6.77-6.74 (m, 2H), 6.72 (dd, J=8.70, 2.70 Hz, 1H), 6.53 (bs, 1H), 4.23(s, 2H), 3.99 (s, 2H), 3.70 (s, 3H), 3.69 (s, 3H), 3.61-3.56 (m, 2H),2.25 (t, J=7.40 Hz, 2H), 1.33 (quint., J=7.70 Hz, 2H). ¹³C NMR (100 MHz,MeOH-d₄) δ 158.97, 154.78, 154.59, 153.92, 134.64, 131.99, 129.03,127.12, 126.97, 123.58, 113.93, 111.89, 107.57, 99.54, 54.78, 54.31,42.77, 29.56, 28.58, 23.59 (broad), 21.71. LCMS (50-95% acetonitrile in0.05% TFA over 10 minutes) retention time=1.75 minutes, ESI m/z=457,[M+H]⁺.

Synthesis of 5-methoxy-3-((5-(3-(trifluoromethyl)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(78)

Prepared according to General Procedure 1C from thioamide C (360 mg,0.63 mmol), 3-(trifluoromethyl)phenylacetic hydrazide (29i) (172 mg,0.79 mmol), silver benzoate (286 mg, 1.26 mmol), and acetic acid (113mg, 108 μL, 1.89 mmol), to afford 932 mg of crude material. The crudewas purified by flash chromatography (SiO₂, 20:1 CH₂Cl₂/MeOH to 10:1)afforded 209 mg (45% yield) of compound 78. ¹H NMR (400 MHz, DMSO-d₆) δ10.7 (s, 1H), 7.90 (d, J=8.20 Hz, 1H), 7.60-7.38 (complex m, 3H), 7.32(m, 9H), 7.19 (s, 1H), 7.11 (d, J=8.70 Hz, 1H), 7.06 (s, 1H), 6.99 (m,6H), 6.91 (apparent d, J=1.80 Hz, 1H), 6.62 (dd, J=8.70, J=2.30 Hz, 1H)6.43 (s, 1H), 4.10 (s, 2H), 4.09 (s, 2H), 3.75 (t, J=7.30 Hz, 2H), 3.59(s, 3H), 2.25 (t, J=6.90 Hz, 2H), 1.42 (J=7.70 Hz, 2H). LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=7.98 minutes,ESI m/z=737, [M+H]⁺.

Synthesis of 3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3-(trifluoromethyl)benzyl)-4H-1,2,4-triazol-3yl)methyl)-5-methoxy-1H-indole(SK-I-57)

Prepared according to General Procedure 1D from5-methoxy-3-((5-(3-(trifluoromethyl)benzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)-methyl)-1H-indole(78) (209 mg, 0.28 mmol) to afford 105 mg (76% yield) of compoundSK-I-57 as a tan solid. ¹H NMR (400 MHz, MeOH-d₄) δ 7.59 7.41 (complexoverlapping m, 5H), 7.31 (d, J=7.80 Hz, 1H), 7.18 (d, J=8.70 Hz, 1H),6.93 (s, 1H), 6.85 (d, J=2.30 Hz, 1H), 6.72 (dd, J=8.70, 2.30 Hz, 1H),6.54 (bs, 1H), 4.25 (s, 2H), 4.16 (s, 2H), 3.70 (s, 3H), 3.69-3.66 (m,2H), 2.28 (t, J=7.30 Hz, 2H), 1.39 (quint., J=7.50 Hz, 2H). LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=1.85 minutes,ESI m/z=495, [M+H]⁺.

Synthesis of6-fluoro-3-((5-(4-fluorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(80)

Synthesized following General Procedure 1C from thioamide J (547 mg,0.98 mmol), 2-(4-fluorophenyl)acetic hydrazide (206 mg, 1.22 mmol),silver benzoate (449 mg, 1.96 mmol), and acetic acid (177 mg, 168 μL,2.94 mmol), which afforded 1.37 mg of crude material. The crude waspurified by flash chromatography (SiO₂, 40:1 CH₂Cl₂/MeOH to 20:1)afforded 327 mg (49% yield) of compound 80. LCMS (50-95% acetonitrile in0.05% TFA over 10 minutes) retention time=4.42 minutes, ESI m/z=675,[M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(SK-I-91)

Prepared according to General Procedure 1D from6-fluoro-34(5-(4-fluorobenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(80) (136 mg, 0.20 mmol) and afforded 51 mg (59% yield) of compoundSK-I-91 as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (bs, 1H),10.95 (s, 1H), 7.51 (s, 1H), 7.38 (dd, J=8.70, 5.5 Hz, 1H), 7.26-7.21(m, 1H), 7.14-7.02 (complex overlapping m, 7H), 6.77 (dt, J=8.70, 2.30Hz, 1H), 6.67 (bs, 1H), 4.09 (s, 2H), 3.97 (s, 2H), 3.71-3.65 (m, 2H),2.32-2.26 (m, 2H), 1.49-1.40 (m, 2H). LCMS (50-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=1.83 minutes, ESI m/z=433, [M+H]⁺.

Synthesis of6-fluoro-345-(4-methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(82)

Prepared according to General Procedure 1C from thioamide C (300 mg,0.54 mmol), 2-(4-methoxyphenyl)acetic hydrazide (29d) (121 mg, 0.67mmol), silver benzoate (247 mg, 1.08 mmol), and acetic acid (97 mg, 93μL, 1.62 mmol), which formed 737 mg of crude material. The crude waspurified by flash chromatography (SiO₂, 40:1 CH₂Cl₂/MeOH to 20:1)afforded 234 mg (63% yield) of compound 82. ¹H NMR (400 MHz, DMSO-d₆) δ10.92 (bs, 1H), 7.91-7.89 (m, 2H), 7.45 (t, J=7.80 Hz, 2H), 7.39-7.30(complex overlapping m, 8H), 7.22 (d, J=1.40 Hz, 1H), 7.11 (d, J=2.30Hz, 1H), 7.01-6.97 (m, 6H), 6.73-6.68 (m, 3H), 6.47 (bs, 1H), 4.08 (s,2H), 3.90 (s, 2H), 3.59 (s, 3H), 3.67-3.63 (m, 2H), 2.25 (t, J=7.30 Hz,2H), 1.41 (apparent quint., J˜7.30 Hz, 2H). LCMS (50-95% acetonitrile in0.05% TFA over 10 minutes) retention time=3.43 minutes, ESI m/z=687,[M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(4-methocybenzyl)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-JH-indole(SK-I-105)

Synthesized according to General Procedure 1D from6-fluoro-3-((5-(4-methoxybenzyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(82) (224 mg, 0.33 mmol) and afforded 111 mg (76% yield) of compoundSK-1-105 as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (bs, 1H),10.95 (bs, 1H), 7.51 (s, 1H), 7.38 (dd, J=8.20, 5.90 Hz, 1H), 7.06-7.03(m, 2H), 6.97 (d, J=8.20 Hz, 2H), 6.79-6.74 (m, 3H), 6.66 (s, 1H), 4.08(s, 2H), 3.90 (s, 2H), 3.64 (s, 3H), 3.62-3.56 (bm, 2H), 2.32-2.24 (bm,2H), 1.48-1.38 (bm, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.40 (d, 1J_(CF)=234 Hz), 158.47, 153.63, 153.53, 136.61 (d, J_(CF)=13.4 Hz),135.18, 130.42, 129.93, 128.79, 124.57 (d, J_(CF)=2.80 Hz), 124.16,120.15 (d, J_(CF)=9.60 Hz), 114.41, 114.11, 109.59, 107.52 (d,J_(CF)=24.9 Hz), 98.88 (d, J_(CF)=25.8 Hz), 55.51, 42.61, 29.96, 29.59,24.94 (broad), 21.84. LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=1.78 minutes, ESI m/z=445, [M+H]⁺.

Synthesis of6-fluoro-34(5-neopentyl-4-(3-(1-trityl-1H-imidazol-4-0propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(84)

(Prepared from the hydrazide hydrochloride; modification of GeneralMethod 1C) To a solution of thioamide M (300 mg, 0.62 mmol) andhydrazide (3m) (189 mg, 0.78 mmol), in CH₂Cl₂ (40 mL) was added silverbenzoate (284 mg, 1.24 mmol) followed immediately with acetic acid (112mg, 106 μL, 1.86 mmol). The black solution (Ag₂S formation) was stirredat room temperature for 16 hrs. LCMS determined minimal reactionprogress was made; TEA (78 mg, 108 μL, 0.78 mmol) was added and thereaction was stirred at room temperature for 18 hrs. LCMS showed furtherreaction progress was made; silver benzoate (284 mg, 1.24 mmol) andacetic acid (112 mg, 106 μL, 1.86 mmol) were added to the reaction,which was allowed to stir at room, temperature for an additional 72hours. The solution was concentrated and the residue was dissolved in1:1 MeOH/CH₂Cl₂ and treated with 1N HCl (1.24 mmol, 1.24 mL). Themixture was stirred for 5 min, treated with diisopropylethylamine (˜10mmol, ˜5 mL) and concentrated. The residue was suspended in MeOH (120mL), filtered through celite (1 inch pad) and concentrated to afford1.11 g of crude material. The crude residue was purified by flashchromatography (SiO2, 40:1 CH₂Cl₂/MeOH to 20:1) to afford 200 mg (51%yield) of compound 84. This compound was not pure but was taken on “asis.” LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=4.62 minutes, ESI m/z=637, [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-neopentyl-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(SK-I-119)

Prepared according to General Procedure 1D from6-fluoro-34(5-neopentyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(84) (186 mg, 0.29 mmol) and afforded 112 mg (97% yield) of compoundSK-I-119 as a pale yellow solid. LCMS (50-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=1.80 minutes, ESI m/z=395, [M+H]⁺.

Synthesis of3,3′4(4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3,5-diyl)bis(methylene))bis(6-fluoro-1H-indole)(86)

(Prepared from the hydrazide hydrochloride; modification of GeneralMethod 1C) To a solution of of thioamide J (300 mg, 0.54 mmol) andhydrazide hydrochloride (3m) (164 mg, 0.68 mmol), in CH₂Cl₂ (40 mL) wasadded silver benzoate (247 mg, 1.08 mmol) followed immediately withacetic acid (97 mg, 93 μL, 1.62 mmol). The black solution (Ag₂Sformation) was stirred at room temperature for 16 hours. LCMS determinedminimal reaction progress was made; TEA (68 mg, 94 μL, 0.68 mmol) wasadded and the reaction was stirred at room temperature for 18 hours.LCMS showed further reaction progress was made; silver benzoate (247 mg,1.08 mmol) and acetic acid (97 mg, 93 μL, 1.62 mmol) were added to thereaction, which was allowed to stir at room temperature for anadditional 72 hours. The solution was concentrated and the residue wasdissolved in 1:1 MeOH:CH₂Cl₂ and treated with 1N HCl (1.08 mmol, 1.08mL). The mixture was stirred for 5 min, treated withdiisopropylethylamine (˜10 mmol, ˜5 mL) and concentrated. The residuewas suspended in MeOH (120 mL), filtered through celite (1 inch pad) andconcentrated to afford 1.18 g of crude material. The crude residue waspurified by flash chromatography (SiO₂, 40:1 CH₂Cl₂/MeOH to 20:1, to10:1) afforded 68 mg (18% yield) of compound 86. LCMS (50-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=4.32 minutes,ESI m/z=714, [M+H]⁺.

Synthesis of3,3-((4-(3-(1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3,5-diyl)bis(methylene))bis(6-fluoro-1H-indole)(SK-I-124)

Prepared following General Procedure 1D from3,3′((4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3,5-diyl)bis(methylene))bis(6-fluoro-1H-indole)(86) (68 mg, 0.095 mmol) and afforded 33 mg (73% yield) of compoundSK-I-124 as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (bs, 1H),10.90 (bs, 1H), 7.48 (s, 1H), 7.36-7.32 (m, 2H), 7.04-7.01 (m, 4H),6.74-6.69 (m, 2H), 6.64 (s, 1H), 4.07 (s, 4H), 3.69 (apparent t, J˜7.30Hz, 2H), 2.30-2.24 (m, 2H), 1.53-1.44 (m, 2H). LCMS (50-95% acetonitrilein 0.05% TFA over 10 minutes) retention time=1.97 minutes, ESI m/z=472,[M+H]⁺.

Example 2: Synthesis of 3,4,5-Trisubstituted-3-Thio-1,2,4-TriazolesSynthesis of 3-1-1-(Triphenylmethyl)-1H-imidazol-4-yl] propylIsothiocyanate (1)

A mixture of N,N-Dicyclohexylcarbodiimide (1.10 g, 5.3 mmol) and CS₂(3.36 mL, 53 mmol) in THE (16 mL) was treated with a solution ofcommercially available N-boc-1,4-diaminobutane (1.0 g, 5.3 mmol) in THE(32 mL). The reaction mixture was stirred overnight under nitrogen.Removal of the solvent under reduce pressure afforded a white solid. Thesolid was triturated with Et₂O (150 mL) and the dicyclohexylthiourea wasfiltered. The filtrate was evaporated to afford a yellow solid. Theresidue was used in the next step without further purification.

Synthesis of tert-butyl (4-isothiocyanatobutyl) carbamate (2)

A mixture of DCC (3.37 g, 16.3 mmol) and CS2 (13.3 g, 174 mmol) in THE(50 mL) was treated with a solution of3-(1-Trityl-1H-imidazol-4-yl)propan-1-amine (6.0 g, 16.3 mmol) in THE(100 mL). The reaction mixture was stirred overnight under nitrogen.Removal of the solvent under reduced pressure afforded a white solid.The solid was triturated with Et₂O (300 mL) and the dicyclohexylthioureawas filtered. The filtrate was evaporated to afford an oil. Flashchromatography on silica gel using EtOAc/hexanes (2:8) gave the desiredcompound 2 (4.8 g, 72%) as a yellow solid.

General Procedure 2A: General Condensation Reactions

The isothiocyanate (1-2) (1 eq.) was added to the desired hydrazide(3a-3l) (1 eq.) in anhydrous THE (minimum for solubilization) and thereaction was stirred at room temperature under N₂ for 18 to 24 hours.The corresponding hydrazinecarbothioamides (14a-l) were obtained afterevaporation of the solvent and appropriate purification.

General Procedure 28: General Cyclization Reactions

The hydrazinecarbothioamide (14a-1) (1 eq.) was dissolved in EtOH (5mL/mmol), and NaOH 1 M (1.5 eq.) is added. The mixture is heated 85° C.for 3 to 4 hours. At the end of the reaction, water was added. Theaqueous layer was washed with DCM, acidified to pH 2 with conc. HCl 1M,and extracted twice with DCM. After evaporation, the3-thiol-1,2,4-triazole (15a-k) was purified by precipitation,recrystallization, flash chromatography, or used without furtherpurification.

General Procedure 2C: Genera/Alkylation of the thiol Reactions

To a mixture of a benzyl bromide derivative (1 eq.) and a cyclizedderivative (15a-k) (1 eq.) in DCM (8 mL/mmol) was added triethylamine (1eq.). The reaction mixture was stirred 5 to 12 hours, and the solventwas evaporated and the residue was partitioned between EtOAc (150 mL)and brine (150 mL). The layers were separated, and the organic layer wasdried (anhydrous MgSO₄), filtered, and concentrated. The reactionmixture was evaporated and purified by chromatography on silica column(gradient DCM to EtOAc or DCM to DCM/MeOH (9:1).

General Procedure 2D: General N-Boc Deprotection Reactions

To a mixture of the N-Boc-protected compound (1 eq.) in DCM (5.5 mL/mmol) was added 6N HCI in iPrOH (5.5 mL/mmol) and the mixture wasstirred at room temperature overnight. The reaction was co-evaporatedthree times with absolute EtOH. The desired deprotected compound wasobtained after purification (recrystallization, or used without furtherpurification).

General Procedure 2E: General Trityl Deprotection Reactions

A mixture of the trityl-protected compound (1 mmol) in DCM (26.5 mL/mmol) was added 1N HCl (10.6 mL/mmol) and the mixture was stirred atroom temperature overnight. The reaction was co-evaporated three timeswith absolute ethanol, and the desired unprotected compound was obtainedafter purification (recrystallization, or used without furtherpurification).

Synthesis of2-(3-(1H-indol-3-yl)propanoyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)hydrazinecarbothioamide(4a)

Prepared according to the General Procedure 2A from compound 1 (2.09 g,5.1 mmol) and hydrazine 3a (942 mg, 4.6 mmol) to afford 2.41 g (77%) ofcompound 14a as a yellow foam: ¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s,1H), 9.71 (s, 1H), 9.13 (s, 1H), 7.76 (m, 1H), 7.51 (d, J=7.6 Hz, 1H),7.40-7.31 (m, 11H), 7.25 (d, J=1.4 Hz, 1H), 7.10-7.02 (m, 8H), 6.96 (t,J=7.8 Hz, 1H), 3.33 (m, 2H, under H₂O peak), 2.94 (m, 2H), 2.46 (m, 2Hunder DMSO), 2.43 (m, 2H), 1.68 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ171.70, 142.38, 140.66, 137.65, 136.27, 129.24, 128.22, 127.96, 126.95,122.23, 120.98, 118.31, 118.22, 117.53, 113.49, 111.38, 74.39, 43.32,34.14, 28.40, 25.17, 20.39. LCMS (50-95% acetonitrile in 0.05% TFA over10 minutes) retention time=3.28 minutes, ESI m/z=613.36 [M+H]⁺.

Synthesis of2-(quinoline-2-carbonyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)hydrazinecarbothioamide (4b)

Prepared according to the General Procedure 2A from compound 3b (415 mg,2.2 mmol) and 1 (1.00 g, 2.4 mmol) to afford 873 mg (66%) of compound10b as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 9.38(s, 1H), 8.55 (d, J=8.7 Hz, 1H), 8.29 (s, 1H), 8.11-8.07 (m, 3H), 7.89(t, J=6.9 Hz, 1H), 7.75 (t, J=6.9 Hz, 1H), 7.40-7.33 (m, 9H), 7.13 (s,1H), 7.08-7.03 (m, 6H), 6.61 (s, 1H), 3.47 (m, 2H), 2.45 (t, J=7.3 Hz,2H), 1.75 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 181.25, 149.54, 145.91,142.33, 140.68, 137.62, 137.54, 130.56, 129.26, 129.16, 128.84, 128.25,128.17, 127.91, 119.00, 117.39, 74.30, 43.58, 28.26, 25.24.

Synthesis of 2-(2-naphthoyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)hydrazine carbothioamide (14c)

Prepared according to the General Procedure 2A from compound 3c (413 mg,2.2 mmol) and 1 (1.00 g, 2.4 mmol) to afford 1.26 g (95%) of compound14c as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (bs, 1H), 9.32(bs, 1H), 8.52 (s, 1H), 8.33 (bs, 1H), 8.00-7.95 (m, 5H), 7.60 (m, 2H),7.35 (m, 10H), 7.04 (m, 7H), 6.61 (s, 1H), 3.46 (m, 2H), 2.45 (m, 2H),1.74 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 165.97, 142.34, 140.67,137.59, 134.33, 131.97, 129.92, 129.18, 128.92, 128.37, 128.19, 127.92,127.77, 127.68, 126.84, 124.41, 117.45, 74.34, 43.51, 28.35, 25.23.

Synthesis of2-(3-phenylpropanoyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyphydrazinecarbothioamide(14d)

Prepared according to the General Procedure 2A from compound 3d (417 mg,2.5 mmol) and 1 (1.04 g, 2.5 mmol) to afford 558 mg (38%) of compound14d as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.68 (s, 1H), 9.12 (s,1H), 7.82 (m, 1H), 7.41-7.33 (m, 9H), 7.27-7.23 (m, 3H), 7.19-7.14 (m,3H), 7.08 (m, 6H), 6.63 (s, 1H), 3.41 (m, 2H), 2.80 (m, 2H), 2.41 (m,2H), 1.72 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 171.17, 142.38, 141.08,140.65, 137.64, 129.23, 128.37, 128.22, 127.97, 125.99, 117.54, 74.39,43.31, 34.90, 30.35, 28.40, 25.15.

Synthesis of2-(1H-indole-3-carbonyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)hydrazine carbothioamide (14e)

Prepared according to the General Procedure 2A from compound 3e (396 mg,2.3 mmol) and 1 (1.02 g, 2.5 mmol) to afford 1.11 g (85% yield) ofcompound 14e as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s,1H), 9.76 (s, 1H), 9.17 (s, 1H), 8.15-8.08 (m, 2H), 7.45 (d, J=8.3 Hz,1H), 7.40-7.33 (m, 9H), 7.18-7.06 (m, 10H), 6.62 (s, 1H), 3.47 (m, 2H),2.42 (m, 2H), 1.75 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 164.36, 142.38,140.73, 137.61, 135.94, 129.22, 128.91, 128.20, 127.94, 126.35, 122.12,120.95, 120.72, 117.45, 111.92, 108.03, 74.36, 67.05, 43.43, 28.48,25.29, 25.16.

Synthesis of 2-benzoyl-N-(3-(1-trityl-1H-imidazol-4-yl)propyl) hydrazinecarbothioamide (14f)

Prepared according to the General Procedure 2A from phenylhydrazide (3f)(305 mg, 2.24 mmol) and 1 (1.009 g, 2.46 mmol) to afford 913 mg (75%yield) of compound 14f as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ10.34 (s, 1H), 9.27 (s, 1H), 8.26 (s, 1H), 7.91 (d, J=6.8 Hz, 2H), 7.56(d, J=7.3 Hz, 1H), 7.47-7.34 (m, 13H), 7.16 (s, 1H), 7.08-7.06 (m, 7H),6.62 (s, 7H), 3.48-3.44 (m, 2H), 2.45 (d, J=7.3 Hz, 2H), 1.74 (m, 2H).¹³C NMR (100 MHz, DMSO-d₆) δ 165.90, 142.36, 140.67, 137.61, 132.48,131.82, 129.22, 128.22, 127.96, 127.80, 117.45, 74.37, 43.54, 28.34,25.24.

Synthesis of2-(2-(1H-indol-3-yl)acetyl)-N-(3-(1-trityl-H-imidazol-4-yl)propyl)hydrazinecarbothioamide (14 g)

Prepared according to the General Procedure 2A from compound 3g (424 mg,2.24 mmol) and 1 (1.009 g, 2.48 mmol) to afford 1.002 g (75% yield) ofcompound 14g as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s,1H), 9.87 (s, 1H), 9.18 (s, 1H), 7.95 (s, 1H), 7.55 (d, J=8.2 Hz, 1H),7.42-7.21 (m, 12H), 7.11-7.02 (m, 7H), 6.96 (m, 1H), 6.65 (s, 1H), 3.56(s, 2H), 3.44 (m, 2H), 2.45 (t, J=7.3 Hz, 2H), 1.72 (m, 2H). ¹³C NMR(100 MHz, DMSO-d₆) δ 142.40, 140.66, 137.69, 136.06, 129.26, 128.24,127.99, 127.23, 123.97, 121.00, 118.78, 118.34, 117.56, 111.31, 108.01,74.42, 43.42, 30.66, 28.36, 25.22.

Synthesis of 2-(1-naphthoyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)hydrazine carbothioamide (14h)

Prepared according to the General Procedure 2A from compound 3h (412 mg,2.2 mmol) and 1 (997 mg, 2.43 mmol) to afford 1.27 g (96%) of compound14h as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 9.39(s, 1H), 8.29 (m, 2H), 8.06 (d, J=8.3 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H),7.90 (d, J=6.9 Hz, 1H), 7.57-7.50 (m, 3H), 7.43-7.35 (m, 11H), 7.09 (m,6H), 6.71 (s, 1H), 3.52 (m, 2H), 3.45-3.43 (m, 2H), 1.79 (m, 2H). ¹³CNMR (100 MHz, DMSO-d₆) δ 168.19, 142.19, 140.07, 128.27, 128.20, 128.04,127.81, 127.58, 117.75, 74.66, 43.43, 28.31, 24.85.

Synthesis of2-(5-fluoro-1H-indole-2-carbonyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)hydrazinecarbothioamide(14i)

Prepared according to the General Procedure 2A from compound 3i (434 mg,2.25 mmol) and 1 (920 mg, 2.25 mmol) to afford 1.09 g (81%) of compound14i as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 10.38(s, 1H), 9.32 (s, 1H), 8.35 (s, 1H), 7.41-7.32 (m, 11H), 7.15 (s, 1H),7.05 (m, 7H), 6.60 (s, 1H), 3.44 (m, 2H), 2.42 (m, 2H), 1.73 (m, 2H).¹³C NMR (100 MHz, DMSO-d₆) δ 160.77, 158.34, 156.02, 142.37, 140.66,137.61, 133.30, 131.37, 129.19, 128.20, 127.93, 127.01, 126.90, 117.39,113.59, (d), 112.59 (d), 103.72, 74.34, 56.06, 54.96, 54.96, 43.62,28.26, 25.29, 18.59.

Synthesis of2-(3-(4-fluorophenyl)propanoyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyphydrazinecarbothioamide(14i)

Prepared according to the General Procedure 2A from compound 3j (356 mg,1.95 mmol) and 1 (813 mg, 1.95 mmol) to afford 994 mg (85%) of compound14j as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.08 (s,1H), 7.83 (s, 1H), 7.37-7.30 (m, 9H), 7.22-7.16 (m, 3H), 7.04 (m, 7H),6.59 (s, 1H), 3.33 (m, 2H, under H₂O), 2.75 (m, 2H), 2.36 (m, 2H), 1.67(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 171.20, 161.96, 159.56, 142.41,140.68, 137.71, 137.23, 130.10, 130.02, 129.30, 128.29, 128.05, 117.63,115.18, 114.93, 74.46, 43.39, 35.02, 29.55, 25.19.

Synthesis of2-(1H-indole-2-carbonyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)hydrazinecarbothioamide(14k)

Prepared according to the General Procedure 2A from compound 3k (349 mg,1.99 mmol) and 1 (815 mg, 1.99 mmol) to afford 815 mg (70% yield) ofcompound 14k as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s,1H), 10.29 (s, 1H), 9.26 (s, 1H), 8.28 (s, 1H), 7.53 (d, J=7.8 Hz, 1H),7.39-7.28 (m, 10H), 7.17-7.13 (m, 3H), 7.02-6.97 (m, 7H), 6.57 (s, 1H),3.47 (m, 2H, under H₂O peak), 2.38 (m, 2H), 1.70 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 164.45, 163.95, 150.26, 150.22, 142.38, 140.64, 140.30,139.62, 137.64, 129.25, 128.25, 128.01, 121.67, 121.06, 117.53, 74.41,43.56, 28.36, 25.22.

Synthesis of2-(2-(5-Fluoro-1H-indol-3-yl)acetyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)hydrazinecarbothioamide(141)

Prepared according to General Procedure 2A from compound 1 (1 g, 2.44mmol) and hydrazide 31 (506 mg, 2.44 mmol) to afford 1.38 g (92%) ofcompound 141 as a yellow foam: ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s,1H), 9.87 (s, 1H), 9.18 (s, 1H), 8.02 (s, 1H), 7.43-7.26 (m, 13H),7.10-7.07 (m, 6H), 6.89 (m, 1H), 6.64 (s, 1H), 3.44 (m, 2H), 2.43 (m,2H), 1.73 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.24, 157.86, 155.59,142.40, 140.63, 137.67, 132.74, 129.25, 128.23, 127.98, 127.52 (d),126.14, 117.55, 112.28, 109.22 (d), 108.34, 103.72 (d), 74.40, 67.05,43.43, 30.59, 28.36, 25.17.

Synthesis of2-(2-(6-fluoro-1H-indol-3-yl)acetyl-N-3-(1-trityl-1H-imidazol-4-yl)propyl)hydrazinecarbo-thioamide(14m)

Prepared according to General Procedure A from compound 1 (1.12 g, 2.73mmol) and hydrazide 3m (567 mg, 2.73 mmol) to afford 1.20 g (71%) ofcompound 14m as a yellow foam: ¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s,1H), 9.85 (s, 1H), 9.14 (s, 1H), 7.97 (s, 1H), 7.50 (m, 1H), 7.41-7.33(m, 9H), 7.25 (d, J=1.4 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.10-7.04 (m,6H), 6.82-6.76 (m, 1H), 6.63 (s, 1H), 3.51 (s, 2H), 2.41 (m, 2H), 1.75(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.26, 160.01, 157.68, 142.39,140.64, 137.68 135.93 (d), 129.24, 128.22, 124.59 (d), 124.11, 119.93(d), 117.55, 108.32, 106.90 (d), 97.36 (d), 74.40, 43.42, 30.58, 28.37,25.21.

Synthesis of 2-(2-phenylacetyl)-N-(3-(1-trityl-1H-imidazol-4-yl)propyl)hydrazinecarbothioamide (14n)

Prepared according to General Procedure A from compound 1 (1.10 g, 2.69mmol) and hydrazide 3n (403 mg, 2.69 mmol) to afford 1.05 g (70%) ofcompound 14n as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (s, 1H),9.05 (s, 1H), 7.94 (s, 1H), 7.35-7.28 (m, 10H), 7.22 (m, 1H), 7.20-7.10(m, 4H), 7.02-6.99 (m, 6H), 6.59 (s, 1H), 3.39 (s, 2H), 3.34 (m, 2H),2.34 (m, 2H), 1.65 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 142.38, 140.65,137.65, 135.49, 129.23, 128.20, 128.15, 127.95, 117.50, 74.37, 43.39,33.37, 28.35, 25.19.

Synthesis of5-(2-(1H-indol-3-ynethyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15a)

Prepared according to the General Procedure 2B from derivative 14a (2.41g, 3.9 mmol). Flash chromatography on silica gel (gradient DCM/MeOH 9:1)afforded the desired product 15a as a yellow foam (1.78 g, 76%): ¹H NMR(400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.37-7.26(m, 11H), 7.17 (d, J=1.4 Hz, 1H), 7.09 (s, 1H), 7.05-6.96 (m, 7H), 6.85(t, J=6.9 Hz, 1H), 3.83 (t, J=8.2 Hz, 2H), 2.99 (m, 4H), 2.41 (t, J=6.9Hz, 2H), 1.82 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 166.65, 152.61,142.86, 140.37, 138.23, 136.69, 129.71, 128.70, 128.43, 127.35, 123.15,121.48, 118.79, 118.70, 118.18, 113.27, 111.90, 74.87, 43.04, 27.80,26.20, 25.39, 22.03. LCMS (25-95% acetonitrile in 0.05% TFA over 10minutes) retention time=7.08 minutes, ESI m/z=595.41 [M+H]⁺. HRMS(ESI+): m/z calculated for C₃₇H₃₅N₆S (M+H)+595.2630, found 595.2638.

Synthesis of5-(quinolin-2-yl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15b)

Prepared according to the General Procedure 2B from compound 14b (873mg, 1.46 mmol) to afford 800 mg (94%) of compound 15b as a white solid:¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (d, J=8.7 Hz, 1H), 8.13 (d, J=8.2 Hz,1H), 8.08-8.02 (m, 2H), 7.77-7.68 (m, 2H), 7.38-7.34 (m, 9H), 7.23 (s,1H), 7.05-7.03 (m, 6H), 6.69 (s, 1H), 4.69 (t, J=7.6 Hz, 2H), 2.63 (t,J=7.3 Hz, CH₂), 2.14-2.07 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 168.41,148.57, 146.46, 145.85, 142.32, 140.13, 137.70, 130.55, 129.19, 128.13,128.04, 127.90, 127.65, 119.76, 117.67, 74.36, 45.24, 27.99, 25.40.

Synthesis of5-(naphthalen-2-yl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15c)

Prepared according to the General Procedure 2B from compound 14c (1.25g, 2.1 mmol) to afford 996 mg (82%) of compound 15c as a white solid: ¹HNMR (400 MHz, DMSO-d₆) δ 8.23 (d, J=0.9 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H),7.95 (d, J=8.2 Hz, 1H), 7.73 (dxd, J=8.2, 1.4 Hz, 1H), 7.63 (t, J=8.2Hz, 1H), 7.55 (d, J=7.3 Hz, 1H), 4.07 (m, 2H), 2.39 (m, 2H), 1.94 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 167.25, 151.29, 137.67, 133.40,132.33, 129.14, 128.73, 128.60, 128.49, 128.11, 127.89, 127.75, 127.70,126.97, 125.17, 123.40, 118.01, 74.28, 56.07, 43.75, 27.31, 24.73,18.59.

Synthesis of 5-phenethyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol (15d)

Prepared according to the General Procedure 2B from 14d (464 mg, 0.81mmol) to afford 418 mg (93%) of compound 15d as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 8.76 (s, 1H), 7.47-7.43 (m, 10H),7.32-7.24 (m, 5H), 7.21-7.15 (m, 8H), 3.91 (t, J=8.2 Hz, 2H), 3.01-2.93(m, 4H), 2.68-264 (m, 2H), 1.95-1.88 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆)δ 166.33, 166.24, 151.75, 147.77, 140.68, 140.31, 136.62, 133.66,132.55, 129.23, 128.61, 128.56, 128.46, 128.37, 128.33, 127.78, 127.55,126.67, 126.25, 119.64, 115.56, 80.57, 41.94, 31.17, 26.49, 26.27,21.24.

Synthesis of 5-(3a,7a-dihydro-1H-indol-3-yl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15e)

Prepared according to the General Procedure 2B from compound 14e (1.09g, 1.90 mmol) to afford 1.00 g (93%) of compound 15e as a white solid:¹H NMR (400 MHz, DMSO-d₆) δ 11.88 (s, 1H), 8.02 (d, J=2.8 Hz, 1H), 7.97(d, J=8.2 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.41-7.37 (m, 9H), 7.25-7.21(m, 1H), 7.17-7.09 (m, 7H), 6.97 (s, 1H), 4.18 (m, 2H), 2.61 (m, 2H),2.00 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 166.11, 147.48, 141.54,137.38, 135.91, 129.19, 128.36, 128.19, 127.77, 127.54, 126.38, 125.28,122.64, 120.60, 120.48, 118.89, 112.03, 100.46, 75.57, 43.24, 26.60,23.46.

Synthesis of5-phenyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15f)

Prepared according to the General Procedure 2B from compound 14f (890mg, 1.63 mmol) to afford 851 mg (99%) of compound 15f as a white solid:¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (m, 2H), 7.39-7.34 (m, 12H), 7.22 (s,1H), 7.04-7.02 (m, 6H), 6.53 (s, 1H), 3.95 (t, J=7.8 Hz, 2H), 2.37 (t,J=7.3 Hz, 2H), 1.85 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 167.70,150.66, 142.32, 140.02, 137.73, 129.25, 128.73, 128.64, 128.20, 127.99,127.58, 117.83, 74.37, 43.16, 28.17, 25.05.

Synthesis of5-((1H-indol-3-yl)methyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15 g)

Prepared according to the General Procedure 2B from compound 14g (1.00g, 1.67 mmol) to afford 829 mg (85%) of compound 15g as a white solid:¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.47 (s, 1H), 7.47-7.39 (m,10H), 7.31-7.28 (m, 2H), 7.14-7.09 (m, 7H), 7.03 (m, 1H), 6.93 (m, 1H),4.19 (m, 2H), 3.86 (t, J=7.3 Hz, 1H), 2.53 (m, 2H), 1.70 (m, 2H). ¹³CNMR (100 MHz, DMSO-d₆) δ 166.46, 151.36, 140.80, 136.62, 136.22, 134.76,129.22, 128.56, 128.49, 127.78, 127.54, 126.65, 124.21, 121.29, 119.33,118.66, 118.29, 111.62, 107.11, 76.68, 42.16, 26.44, 22.19, 21.92.

Synthesis of5-(naphthalen-1-0-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15h)

Prepared according to the General Procedure 2B from compound 14h (1.11g, 1.86 mmol) to afford 733 mg (69%) of 15h as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.11 (d, J=8.2 Hz, 1H), 8.04 (d,J=7.8 Hz, 1H) 7.80 (d, J=7.1 Hz, 1H), 7.62-7.54 (m, 4H), 7.41-7.37 (m,10H), 7.08 (s, 1H), 7.02 (m, 6H), 3.70 (m, 2H), 2.44 (m, 2H), 1.74 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 166.84, 149.71, 140.16, 136.32,132.98, 132.69, 131.30, 131.23, 129.33, 129.18, 128.71, 127.93, 126.98,125.44, 124.28, 122.92, 120.22, 77.43, 42.55, 26.47, 20.87.

Synthesis of5-(5-fluoro-1H-indol-2-0-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(151)

Prepared according to the General Procedure 2B from compound 14i (1.09g, 1.81 mmol) to afford 410 mg (39%) of 15i as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 11.96 (s, 1H), 7.44-7.41 (m, 1H), 7.36-7.34 (m,10H), 7.19-7.16 (m, 1H), 7.09-7.05 (m, 8H), 6.95 (s, 1H), 6.72 (s, 1H),4.23 (m, 2H), 2.58 (m, 2H), 2.02 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ166.84, 149.71, 140.16, 136.32, 132.98, 132.69, 131.30, 131.23, 129.33,129.18, 128.71, 127.93, 126.98, 125.44, 124.28, 122.92, 120.22, 77.43,42.55, 26.47, 20.87.

Synthesis of5-(4-fluorophenethyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15j)

Prepared according to the General Procedure 2B from compound 14j (893mg, 1.51 mmol) to afford 790 mg (91%) of 15j as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 7.97 (s, 1H), 7.34-7.28 (m, 9H), 7.20-7.16 (m, 2H),7.04-6.92 (m, 9H), 3.78 (m, 2H), 2.47 (m, 2H), 1.79 (m, 2H). ¹³C NMR(100 MHz, DMSO-d₆) δ 166.24, 162.05, 159.64, 151.61, 147.80, 141.21,136.94, 136.43, 133.61, 132.38, 130.35 (d), 129.24, 128.50 (d), 127.81,127.57, 126.68, 119.09, 115.09 (d), 76.14, 42.07, 30.26, 26.78, 26.33,22.85.

Synthesis of5-(1H-indol-2-0-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15k)

Prepared according to the General Procedure 2B from 14k (735 mg, 1.26mmol) to afford 610 mg (86%) of compound 15k as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 11.87 (s, 1H), 8.79 (s, 1H), 7.55 (d, J=8.3 Hz,1H), 7.45-7.35 (m, 12H), 7.22-7.10 (m, 7H), 7.06-6.99 (m, 2H), 4.23 (m,2H), 2.75 (m, 2H), 2.04 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 167.28,147.80, 145.17, 140.51, 136.80, 136.56, 133.63, 129.25, 128.65, 127.81,127.58, 127.48, 126.69, 123.71, 122.43, 120.20, 120.04, 112.05, 103.31,77.16, 43.13, 26.54, 25.17.

Synthesis of5-((5-Fluoro-1H-indol-3-yl)methyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(151)

Prepared according to General Procedure 2B from derivative 141 (1.23 g,2.00 mmol). Evaporation of the organic phase afforded the desiredproduct 151 as a yellow foam (860 mg, 72%): 1C NMR (400 MHz, DMSO-d₆) δ11.19 (s, 1H), 7.48-7.39 (m, 10H), 7.32-7.21 (m, 3H), 7.17-7.14 (m, 6H),6.90 (s, 1H), 4.17 (s, 2H), 3.86 (d, J=7.4 Hz, 2H), 2.61 (d, J=7.3 Hz,2H), 1.76 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 166.49, 157.82, 155.52,151.24, 147.78, 140.47, 136.39, 133.66, 132.89, 129.23, 128.66, 127.79,127.55, 127.00 (d), 126.67, 126.34, 119.77, 112.71 (d), 109.58 (d),107.40 (d), 103.21 (d), 77.20, 42.02, 26.36, 21.74, 21.62.

Synthesis of5-((6-fluoro-1H-indol-3-yl)methyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15m)

Prepared according to General Procedure B from derivative 14m (1.50 g,2.40 mmol) to afford the desired product 15m as a yellow foam (1.46 g,quantitative yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H), 8.59 (s,1H), 7.47-7.39 (m, 11H), 7.33 (s, 1H), 7.18-7.08 (m, 8H), 6.82 (s, 1H),4.19 (s, 2H), 3.86 (m, 2H), 2.60 (m, 2H), 1.75 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 166.48, 160.05, 157.72, 151.21, 140.73, 136.58, 136.17(d), 129.21, 128.58, 128.51, 124.86 (d), 123.55, 119.45 (d), 107.42,107.34 (d), 97.70, 97.44, 76.80, 42.11, 26.41, 22.05, 21.81.

Synthesis of5-benzyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15n)

Prepared according to General Procedure B from derivative 14n (879 mg,1.55 mmol) to afford the desired product 15n as a yellow foam (703 mg,84%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.45-7.39 (m, 9H),7.27-7.22 (m, 4H), 7.17-7.11 (m, 7H), 6.92 (s, 1H), 4.10 (s, 2H), 3.83(m, 2H), 2.53 (m, 2H), 1.68 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ166.60, 151.15, 141.30, 136.98, 135.07, 129.21, 128.73, 128.63, 128.44,128.32, 127.02, 118.75, 42.40, 30.72, 26.58, 23.08.

Synthesis of6-fluoro-345-(3-methylbenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-JH-indole(16m)

Prepared according to General Procedure C from cyclized compound 15m(690 mg, 1.15 mmol) and benzyl bromide (138 μL, 1.15 mmol) to afford 500mg (63%) of the desired product 16m as a yellow foam: ¹H NMR (400 MHz,DMSO-d₆) δ 11.03 (s, 1H), 7.47-7.43 (m, 1H), 7.40-7.35 (m, 9H), 7.24 (s,1H), 7.16-7.04 (m, 13H), 6.79 (m, 1H), 6.54 (s, 1H), 4.26 (s, 2H), 4.17(s, 2H), 3.61 (t, J=7.8 Hz, 2H), 2.27 (t, J=7.1 Hz, 2H), 1.48 (m, 2H).¹³C NMR (100 MHz, DMSO-d₆) δ 160.05, 157.73, 154.40, 148.36, 142.31,139.56, 137.72, 137.21, 136.19, 136.07, 129.17, 128.73, 128.31, 128.16,127.93, 127.32, 124.18, 123.60, 119.62 (d), 117.53, 108.76 (d), 107.14(d), 97.51 (d), 74.35, 42.66, 37.60, 28.66, 24.59, 21.56.

Synthesis of6-fluoro-345-(3-methylbenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(17m)

Prepared according to General Procedure C from cyclized compound 15m(770 mg, 1.29 mmol) and 3-methylbenzyl bromide (174 μL, 1.29 mmol) toafford 545 mg (60%) of the desired product 17m as a yellow foam: ¹H NMR(400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 7.47-7.43 (m, 1H), 7.39-7.36 (m,10H), 7.24 (m, 1H), 7.15 (m, 1H), 7.07-6.93 (m, 11H), 6.78 (m, 1H), 6.54(s, 1H), 4.23 (s, 2H), 4.16 (s, 2H), 3.64 (t, J=7.8 Hz, 2H), 2.28 (t,J=6.9 Hz, 2H), 2.13 (s, 3H), 1.47 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ160.07, 157.75, 154.40, 148.50, 142.31, 139.53, 137.73 (d), 137.02,136.21 (d), 129.35, 129.18, 128.25, 128.18, 128.03, 127.95, 125.85,124.17 (d), 123.61, 119.63 (d), 117.56, 108.81, 107.16 (d), 97.54 (d),74.40, 42.72, 37.53, 28.69, 24.59, 21.54, 20.79.

Synthesis of3-benzyl-5-(benzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole(17n)

Prepared according to General Procedure C from cyclized compound 15n(333 mg, 0.61 mmol) and 3-methoxybenzyl bromide (86 μL, 0.61 mmol) toafford 266 mg (65%) of the desired product 17n as a white foam: ¹H NMR(400 MHz, DMSO-d₆) δ 7.39-7.36 (m, 10H), 7.23-7.19 (m, 4H), 7.11-7.02(m, 9H), 6.80-6.73 (m, 2H), 6.49 (s, 1H), 4.26 (s, 2H), 4.08 (s, 2H),3.63 (s, 3H), 3.60 (m, 2H), 2.26 (m, 2H), 1.40 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 159.16, 154.31, 148.66, 142.32, 139.50, 138.67, 137.73,136.27, 129.46, 129.18, 128.51, 128.37, 128.18, 127.97, 126.70, 120.97,117.55, 114.26, 11305, 74.37, 42.80, 37.41, 30.39, 28.73, 24.64.

Synthesis of3-(3-methoxybenzylthio)-5-phenethyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole(17d)

Prepared according to General Procedure C from cyclized compound 15d(401 mg, 0.72 mmol) and 3-methoxybenzyl bromide (101 μL, 0.72 mmol) toyield 420 mg (88%) of 17d as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ7.39-7.33 (m, 9H), 7.21 (d, J=1.4 Hz, 1H), 7.20-7.11 (m, 6H), 7.04-7.02(m, 6H), 6.81-6.75 (m, 3H), 6.58 (s, 1H), 4.25 (s, 2H), 3.66-3.62 (m,2H), 3.65 (s, 3H), 2.97-2.86 (m, 4H), 2.36-2.33 (m, 2H), 1.67-1.63 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.17, 154.90, 148.11, 142.31,140.62, 139.55, 138.71, 137.76, 129.50, 129.18, 128.37, 128.24, 128.19,127.96, 126.11, 121.02, 117.74, 114.33, 113.00, 74.37, 42.42, 37.29,32.47, 28.79, 26.21, 24.50.

Synthesis of3-(2-(5-(benzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(S16a)

Prepared according to the General Procedure 2C from cyclized compound15a (272 mg, 0.46 mmol) and benzyl bromide (55 μL, 0.46 mmol) to afford218 mg (70%) of 16a as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.78(bs, 1H), 7.44 (d, J=7.8 Hz, 2H), 7.36-7.32 (m, 9H), 7.30 (d, J=8.2 Hz,1H), 7.23-7.19 (m, 6H), 7.10 (m, 1H), 7.04-7.01 (m, 7H), 6.89 (t, J=7.6Hz, 1H), 6.56 (s, 1H), 4.27 (s, 2H), 3.64 (t, J=7.8 Hz, 2H), 3.06-2.95(m, 4H), 2.33 (t, J=6.8 Hz, 2H), 1.64 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 155.41, 147.03, 142.31, 139.50, 137.78, 137.22, 136.18,129.18, 128.86, 128.42, 128.17, 127.94, 127.42, 126.89, 122.61, 120.93,118.25, 118.15, 117.66, 113.15, 111.35, 74.36, 42.51, 37.40, 28.87,25.53, 24.59, 22.64. LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=5.28 minutes, ESI m/z=685.44 [M+H]⁺.

Synthesis of3-(2-(5-(3-chlorobenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(17a)

Prepared according to the General Procedure 2C from cyclized compound15a (323 mg, 0.54 mmol) and 3-chlorobenzyl bromide (71 μL, 0.54 mmol) toafford 320 mg (82%) of 17a as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ10.79 (s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.36-7.33 (m, 9H), 7.30-7.20 (m,4H), 7.11 (d, J=3.5 Hz, 1H), 7.04-7.01 (m, 8H), 6.87 (m, 1H), 6.58 (s,1H), 4.29 (s, 2H), 3.64 (m, 2H), 3.06-2.96 (m, 4H), 2.32 (m, 2H), 1.66(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 155.57, 147.82, 142.32, 140.05,139.49, 137.83, 136.19, 132.89, 130.26, 129.19, 128.71, 128.19, 127.96,127.61, 127.35, 126.89, 122.62, 120.94, 118.27, 118.15, 117.67, 113.16,111.38, 74.37, 42.56, 36.42, 28.89, 25.55, 24.58, 22.65.

Synthesis of3-(3-methoxybenzylthio)-5-phenethyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole(17d)

Prepared according to General Procedure C from cyclized compound 15d(401 mg, 0.72 mmol) and 3-methoxybenzyl bromide (101 μL, 0.72 mmol) toyield 420 mg (88%) of 17d as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ7.39-7.33 (m, 9H), 7.21 (d, J=1.4 Hz, 1H), 7.20-7.11 (m, 6H), 7.04-7.02(m, 6H), 6.81-6.75 (m, 3H), 6.58 (s, 1H), 4.25 (s, 2H), 3.66-3.62 (m,2H), 3.65 (s, 3H), 2.97-2.86 (m, 4H), 2.36-2.33 (m, 2H), 1.67-1.63 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.17, 154.90, 148.11, 142.31,140.62, 139.55, 138.71, 137.76, 129.50, 129.18, 128.37, 128.24, 128.19,127.96, 126.11, 121.02, 117.74, 114.33, 113.00, 74.37, 42.42, 37.29,32.47, 28.79, 26.21, 24.50.

Synthesis of3-(2-(5-(3-fluorobenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-ynethyl)-1H-indole(18a)

Prepared according the General Procedure 2C from 15a (300 mg, 0.51 mmol)and 3-fluorobenzyl bromide (62 μL, 0.51 mmol) to afford 250 mg (73%) ofcompound 18a as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s,1H), 7.41 (d, J=7.8 Hz, 1H), 7.34-7.19 (m, 12H), 7.18 (d, J=1.4 Hz, 1H),7.10-7.04 (m, 2H), 7.01-6.96 (m, 8H), 6.85 (m, 1H), 6.54 (s, 1H), 4.27(s, 2H), 3.64 (d, J=7.8 Hz, 2H), 3.05-2.83 (m, 4H), 2.31 (t, J=6.8 Hz,2H), 1.64 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 207.10, 163.71, 161.24,156.05, 148.36, 142.82, 140.76 (2), 140.00, 138.32, 136.69, 130.84 (2),129.68, 128.68, 128.45, 127.39, 125.51, 123.11, 121.44, 118.76, 118.65,118.18, 116.26, 116.04, 114.86, 114.65, 113.65, 111.88, 74.86, 43.06,37.00, 31.23, 29.42, 26.05, 25.07, 23.15. LCMS (60-95% acetonitrile in0.05% TFA over 10 minutes) retention time=2.77 minutes, ESI m/z=703.38[M+H]⁺.

Synthesis of3-(2-(5-(3,4-dichlorobenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(19a)

Prepared according the General Procedure 2C from 15a (526 mg, 0.88 mmol)and 3,4-dichlorobenzyl bromide (128 μL, 0.88 mmol) to afford 218 mg(70%) of compound 19a as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ10.75 (s, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.41 (d,J=7.8 Hz, 1H), 7.34-7.21 (m, 11H), 7.18 (d, J=1.4 Hz, 1H), 7.08 (d,J=2.3 Hz, 1H), 7.01-6.96 (m, 7H), 6.86 (t, J=7.3 Hz, 1H), 6.56 (s, 1H),4.27 (s, 2H), 3.66 (t, J=7.3 Hz, 2H), 3.05-2.92 (m, 4H), 2.32 (t, J=6.8Hz, 2H), 1.66 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 207.08, 156.14,142.82, 139.99, 139.38*2, 138.34, 136.69, 131.34, 131.03, 130.51,129.79, 129.72, 128.44, 128.16, 127.41*2, 123.15, 121.44, 118.78*2,118.57, 118.19, 113.64, 74.87, 43.11, 36.10, 29.45, 26.02, 25.03, 23.10.LCMS (60-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=2.67 minutes, ESI m/z=753.36 [M+H]⁺.

Synthesis of345-(4-bromobenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(190)

Prepared according to General Procedure C from cyclized compound 15g(500 mg, 0.86 mmol) and 4-bromobenzyl bromide (215 mg, 0.86 mmol) toafford 506 mg (78%) of 19o as a yellow foam: ¹H NMR (400 MHz, DMSO-d₆) δ10.94 (s, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.40-7.34 (m, 9H), 7.31 (d, J=7.8Hz, 1H), 7.24-7.22 (m, 2H), 7.19 (m, 1H), 7.10-7.01 (m, 9H), 6.91 (t,J=7.8 Hz, 1H), 6.54 (s, 1H), 4.23 (s, 2H), 4.18 (s, 2H), 3.61 (t, J=7.5Hz, 2H), 2.26 (t, J=6.8 Hz, 2H), 1.49 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 154.68, 148.11, 142.31, 139.54, 137.73, 136.85, 136.27,131.18, 130.88, 129.18, 128.17, 127.93, 126.71, 123.64, 121.16, 120.52,118.51, 118.47, 117.57, 111.50, 108.32, 74.36, 42.66, 36.65, 28.73,24.57, 21.70.

Synthesis of Methyl4-((5-((1H-indol-3-yl)methyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-ylthio)methyl)benzoate(20o)

Prepared according to General Procedure C from cyclized compound 15g(493 mg, 0.85 mmol) and methyl 4-(bromomethyl)benzoate (194 mg, 0.85mmol) to afford 395 mg (64%) of 20o as a yellow foam: ¹H NMR (400 MHz,DMSO-d₆) δ 10.87 (s, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz,1H), 7.35-7.31 (m, 9H), 7.26-7.23 (m, 3H), 7.18 (m, 1H), 7.14 (d, J=2.3Hz, 1H), 7.03-6.96 (m, 7H), 6.85 (t, J=7.3 Hz, 1H), 6.49 (s, 1H), 4.29(s, 2H), 4.13 (s, 2H), 3.78 (s, 3H), 3.58 (t, J=7.8 Hz, 2H), 2.21 (t,J=6.8 Hz, 2H), 1.44 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 165.87,154.72, 148.02, 142.95, 142.32, 139.54, 137.71, 136.26, 129.21, 129.17,129.05, 128.51, 128.16, 127.92, 126.69, 123.63, 121.16, 118.47, 117.57,111.48, 108.30, 74.35, 52.10, 42.68, 38.87, 36.94, 28.75, 24.55, 21.68.

Synthesis of3-benzyl-5-(benzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole(16n)

Prepared according to General Procedure C from cyclized compound 15n(370 mg, 0.68 mmol) and benzyl bromide (82 μL, 0.68 mmol) to afford 252mg (58%) of the desired product 16n as a white foam: ¹H NMR (400 MHz,DMSO-d₆) δ 7.40-7.35 (m, 10H), 7.23-7.08 (m, 10H), 7.04-7.02 (m, 6H),6.48 (s, 1H), 4.27 (s, 2H), 4.07 (s, 2H), 3.57 (t, J=7.6 Hz, 2H), 2.28(t, J=7.2 Hz, 2H), 1.39 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.32,148.65, 142.32, 139.50, 137.73, 137.21, 136.26, 129.20, 128.80, 128.53,128.39, 128.20, 128.00, 127.39, 126.71, 117.57, 74.39, 42.76, 37.57,30.40, 28.67, 24.64.

Synthesis of2-(5-(benzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)quinoline(16b)

Prepared according to the General Procedure 2C from 15b (550 mg, 0.95mmol) to afford 460 mg (72%) of compound 16b as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 8.54 (d, J=8.7 Hz, 1H), 8.30 (d, J=8.7 Hz, 1H),8.05 (d, J=6.9 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.75-7.55 (m, 5H),7.37-7.19 (m, 13H), 7.05-7.01 (m, 5H), 6.62 (s, 1H), 4.49 (m, 2H), 4.48(m, 2H), 2.54 (m, 2H), 1.97 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ152.42, 152.26, 147.16, 146.59, 142.30, 139.77, 137.77, 137.42, 137.06,130.33, 129.17, 128.97, 128.47, 128.11, 127.99, 127.92, 127.60, 127.53,127.37, 119.93, 117.72, 74.35, 45.50, 36.80, 29.26, 25.13.

Synthesis of2-(5-(2-(1H-indol-3-ynethylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)quinoline(17b)

The cyclized compound 15b (515 mg, 0.89 mmol) was dissolved in DMF (7.1mL) followed by the addition of K2CO3 (123 mg, 0.89 mmol) and3-(2-bromoethyl)-1H-indole (199 mg, 0.89 mmol). The reaction was stirredat 40° C. overnight and the precipitate was filtered and washed withcold diethyl ether to afford 496 mg (77%) of 17b as a brown solid: ¹HNMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 8.53 (d, J=8.7 Hz, 1H), 8.29 (d,J=8.7 Hz, 1H), 8.04 (d, J=6.9 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.74-7.60(m, 3H) 7.35-7.32 (m, 10H), 7.25-7.23 (m, 2H), 7.08-6.95 (m, 8H), 6.66(s, 1H), 4.57 (m, 2H), 3.55 (m, 2H), 3.16 (m, 2H), 2.59 (m, 2H), 2.10(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 152.66, 150.01, 147.78, 146.40,143.79, 143.65, 138.67, 133.63, 133.53, 133.53, 132.13, 131.38, 129.50,129.22, 128.27, 127.91, 127.79, 127.55, 127.00, 126.66, 124.40, 120.63,120.32, 119.58, 115.80, 112.00, 105.17, 80.57, 48.00, 30.43, 27.94,27.81, 21.12.

Synthesis of2-(5-(3-Bromobenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-Aquinoline(18b)

Prepared according to General Procedure 2C from cyclized compound 15b(480 mg, 0.83 mmol) and 3-bromobenzyl bromide (207 mg, 0.83 mmol) toafford 325 mg (52%) of 18b as a white foam: ¹H NMR (400 MHz, DMSO-d₆) δ8.54 (d, J=8.2 Hz, 1H), 8.30 (d, J=8.7 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H),7.99 (d, J=7.8 Hz, 1H), 7.75-7.64 (m, 2H), 7.60 (m, 1H), 7.41-7.32 (m,11H), 7.25-7.20 (m, 2H), 7.05-7.01 (m, 6H), 6.64 (s, 1H), 4.49 (m, 4H),2.55 (m, 2H), 1.99 (m, 2H). 13H NMR (100 MHz, DMSO-d₆) δ 152.51, 151.98,147.11, 146.57, 142.29, 140.13, 139.73, 137.79, 137.40, 131.65, 130.54,130.30, 129.16, 128.09, 127.96, 127.90, 127.58, 127.35, 121.52, 119.91,117.70, 74.33, 45.53, 35.80, 29.26, 25.12.

Synthesis of3-(benzylthio)-5-(naphthalen-2-yl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole(16c)

Prepared according to the General Procedure 2C from compound 15b (417mg, 0.72 mmol) to afford 270 mg (56%) of 16c as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.92 (d,J=8.2 Hz, 1H), 7.69 (dxd, J=8.2, 1.4 Hz, 1H), 7.59 (t, J=6.9 Hz, 1H),7.51 (d, J=6.9 Hz, 1H), 7.34-7.19 (m, 14H), 7.14 (d, J=1.4 Hz, 1H), 7.14(d, J=1.4 Hz, 1H), 6.92-6.90 (m, 6H), 6.45 (s, 1H), 4.42 (s, 2H), 3.88(t, J=6.8 Hz, 2H), 2.31 (t, J=6.4 Hz, 2H), 1.75 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 154.95, 150.19, 142.20, 139.16, 137.85, 137.15, 133.11,132.45, 129.19, 128.99, 128.58, 128.50, 128.10, 127.90, 127.66, 127.53,127.40, 126.83, 125.39, 124.57, 117.97, 74.28, 43.82, 28.81, 24.50.

Synthesis of3-(benzylthio)-5-phenethyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole(16d)

Prepared according to the General Procedure 2C from compound 15d (388mg, 0.70 mmol) to afford 335 mg (74%) of 16d as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 7.37 (m, 9H), 7.24-7.19 (m, 10H), 7.14 (m, 1H),7.06-7.03 (m, 6H), 6.59 (s, 1H), 4.30 (s, 2H), 2.97-2.87 (m, 4H), 2.36(m, 2H), 1.65 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.88, 148.11,142.30, 140.62, 139.55, 137.76, 137.25, 129.18, 128.85, 128.40, 128.38,128.23, 128.18, 127.96, 127.42, 126.10, 117.74, 74.38, 42.41, 37.34,32.46, 28.76, 26.20, 24.51.

Synthesis of3-(5-(benzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)-1H-indole(16e)

Prepared according to the General Procedure 2C from compound 15e (457mg, 0.81 mmol) to afford 423 mg (80%) of 16e as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.81 (d,J=2.8 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.34-7.30 (m, 11H), 7.28 (s, 1H),7.25-7.10 (m, 4H), 7.04-7.02 (m, 6H), 6.59 (s, 1H), 4.37 (s, 2H), 3.88(t, J=8.2 Hz, 1H), 2.42 (t, J=6.8 Hz, 2H), 1.77 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 171.70, 142.38, 140.66, 137.65, 136.27, 129.24, 128.22,127.96, 126.95, 122.23, 120.98, 118.31, 118.22, 117.53, 113.49, 111.38,74.39, 43.32, 34.14, 28.40, 25.17, 20.39.

Synthesis of3-(benzylthio)-5-phenyl-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole(16f)

Prepared according to the General Procedure 2C from 15f (810 mg, 1.53mmol) to afford 440 mg (460%) of 16f as a white solid: ¹H NMR (400 MHz,DMSO-d₆) δ 7.55 (m, 2H), 7.47-7.42 (m, 3H) 7.37-7.19 (m 15H), 7.04-7.00(m, 6H), 6.48 (s, 1H), 4.41 (s, 2H), 3.81 (t, J=7.8 Hz, 2H), 2.30 (t,J=6.8 Hz, 2H), 1.70 (in, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.95,149.99, 142.27, 139.13, 137.87, 137.14, 129.99, 129.22, 129.00, 128.93,128.51, 128.36, 128.20, 128.02, 127.56, 127.27, 117.92, 74.39, 43.60,37.34, 28.82, 24.48.

Synthesis of3-((5-(benzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(16 g)

Prepared according to the General Procedure 2C from 15 g (775 mg, 1.37mmol) to afford 647 mg (720%) of compound 16g as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 10.93 (s, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.40-7.35(m, 9H), 7.30-7.25 (m, 2H), 7.15-7.01 (m, 13H), 6.91 (s, 1H), 6.53 (s,1H), 4.25 (s, 2H), 4.17 (s, 2H), 3.59 (t, J=7.3 Hz, 2H), 2.24 (t, J=7.3Hz, 2H), 1.45 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.62, 148.38,142.30, 139.45, 137.72, 137.23, 136.30, 129.21, 128.75, 128.36, 128.22,128.00, 127.36, 126.74, 123.61, 121.24, 118.53, 117.62, 111.47, 108.44,74.45, 42.68, 37.68, 28.69, 24.57, 21.69.

Synthesis of3-((5-(3-(trifluoromethyl)benzylthio)-4-(3-(J-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(17 g

Prepared according to the General Procedure 2C from compound 15g (468mg, 0.81 mmol) and 3-trifluoromethylbenzyl bromide (123 μL, 0.81 mmol)to afford 474 mg (80%) of compound 17g as a pale yellow foam: ¹H NMR(400 MHz, DMSO-d₆) δ 10.88 (d, J=2.3 Hz, 1H), 7.60 (s, 1H), 7.39-6.97(m, 24H), 6.46 (d, 1H), 4.34 (s, 2H), 4.12 (s, 2H), 3.61 (t, J=7.4 Hz,2H), 2.21 (t, J=7.1 Hz, 2H), 1.40 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ154.83, 148.13, 142.37, 139.55, 139.15, 137.81, 136.31, 132.97, 129.42,129.24, 129.01, 128.25, 128.03, 126.76, 125.49 (d), 124.07 (d), 123.66,122.76, 121.29, 118.53 (d), 117.64, 111.53, 108.44, 74.45, 42.82, 36.46,28.76, 24.61, 21.65.

Synthesis of3-((5-(3-fluorobenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-IH-indole (18d)

Prepared according to the General Procedure 2C from compound 15g (529mg, 0.91 mmol) and 3-fluorobenzyl bromide (112 μL, 0.91 mmol) to afford610 mg (97%) of 18 g as a pale yellow foam: ¹H NMR (400 MHz, DMSO-d₆) δ10.93 (s, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.40-7.34 (m, 10H), 7.29-7.23 (m,2H), 7.14-6.98 (m, 12H), 6.90 (s, 1H), 6.53 (s, 1H), 4.30 (s, 2H), 4.18(s, 2H), 3.66 (t, J=7.8 Hz, 2H), 2.26 (t, J=7.3 Hz, 2H), 1.48 (m, 2H).¹³C NMR (100 MHz, DMSO-d₆) δ 163.11, 160.68, 154.68, 148.14, 142.32,140.23 (d), 139.54, 137.72, 136.24, 130.26 (d), 129.17, 128.16, 127.92,124.89, 123.57, 121.18, 118.47, 117.54, 115.69 (d), 114.29 (d), 111.43,108.42, 74.35, 42.75, 36.56, 28.75, 24.58, 21.60.

Synthesis of3-((5-(3,4-dichlorobenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(19 g)

Prepared according to the General Procedure 2C from 15 g (519 mg, 0.89mmol) and 3,4-dichlorobenzyl bromide (130 μL, 0.89 mmol) to afford 538mg (81%) of compound 19g as a pale yellow foam: ¹H NMR (400 MHz,DMSO-d₆) δ 10.93 (s, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.45-7.00 (m, 23H),6.90 (m, 1H), 6.54 (s, 1H), 4.29 (s, 2H), 4.18 (s, 2H), 3.68 (t, J=7.6Hz, 2H), 2.28 (t, J=6.9 Hz, 2H), 1.50 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 154.78, 147.98, 142.32, 139.54, 138.80, 137.75 136.26,130.83, 130.81, 130.38, 129.97, 129.19, 129.08, 128.16, 127.93, 126.71,123.64, 121.18, 118.49, 117.58, 111.48, 108.36, 74.36, 42.77, 35.68,28.78, 24.57, 21.64.

Synthesis of3-((5-(3-bromobenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(20 g)

Prepared according to the General Procedure 2C from 15 g (510 mg, 0.88mmol) and 3-bromobenzyl bromide (219 mg, 0.88 mmol) to afford 544 mg(83%) of 20 g as a pale yellow foam: ¹H NMR (400 MHz, DMSO-d₆) δ 10.92(s, 1H), 7.48-7.00 (m, 24H), 6.92 (m, 1H), 6.53 (s, 1H), 4.28 (s, 2H),4.17 (s, 2H), 3.68 (t, J=7.8 Hz, 2H), 2.27 (t, J=7.1 Hz, 2H), 1.47 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.71, 148.11, 142.32, 140.27,139.52, 137.74 136.25, 131.54, 130.41, 130.16, 129.19, 128.17, 127.94,127.84, 126.71, 123.60, 121.49, 121.19, 118.49, 117.56, 111.45, 108.42,74.36, 42.77, 36.40, 28.74, 24.60, 21.61.

Synthesis of3-(benzylthio)-5-(naphthalen-1-yl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole(16h)

Prepared according to the General Procedure 2C from 15h (733 mg, 1.3mmol) to afford 310 mg (37%) of compound 16h as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 7.98-7.92 (m, 2H), 7.53-7.45 (m, 4H), 7.33-7.19 (m,15H), 7.00 (m, 1H), 6.92-6.88 (m, 6H), 6.21 (s, 1H), 4.37 (s, 2H), 3.46(m, 2H), 2.02 (m, 2H), 1.39 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ153.65, 149.32, 142.23, 139.04, 137.62, 137.32, 133.00, 131.46, 130.50,129.16, 129.01, 128.69, 128.55, 128.48, 128.17, 127.98, 127.56, 127.34,126.63, 125.28, 124.62, 124.55, 117.56, 74.29, 59.83, 43.43, 28.91,24.32.

Synthesis of2-(5-(benzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole(16i)

Prepared according to the General Procedure 2C from 15i (340 mg, 0.58mmol) to yield 156 mg (39%) of compound 16i as a pale yellow foam: ¹HNMR (400 MHz, DMSO-d₆) δ 11.96 (s, 1H), 7.40-7.37 (m, 1H), 7.30-7.25 (m,12H) 7.21-7.10 (m 4H), 7.01-6.99 (m, 7H), 6.74 (s, 1H), 6.58 (s, 1H),4.38 (s, 2H), 3.96 (m, 2H), 2.43 (m, 2H), 1.78 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 158.31, 155.99, 150.44, 148.67, 142.30, 139.27, 138.02,137.09, 133.31, 129.21, 128.97, 128.51, 128.19, 128.01, 127.58, 125.55,118.23, 113.05, 112.94, 111.74, 111.49, 105.27, 105.04, 101.53, 74.44,43.89, 37.49, 28.54, 24.59.

Synthesis of3-(benzylthio)-5-(4-fluorophenethyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole(16j)

Prepared according to the General Procedure 2C from compound 15j (740mg, 1.29 mmol) and benzyl bromide (154 μL, 1.29 mmol) to afford 636 mg(74%) of 16j as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.39-7.35 (m,9H), 7.25-7.19 (m, 8H) 7.05-6.97 (m, 8H), 6.59 (s, 1H), 4.28 (s, 2H),3.65 (m, 2H), 2.96-2.84 (m, 4H), 2.35 (m, 2H), 1.65 (m, 2H). ¹³C NMR(100 MHz, DMSO-d₆) δ 161.99, 159.59, 154.79, 148.18, 142.33, 139.57,137.81, 137.28, 136.78, 130.29, 130.21, 129.21, 128.89, 128.44, 128.22,128.01, 128.47, 117.79, 115.02, 114.81, 74.40, 42.42, 37.33, 31.49,28.80, 26.25, 24.51.

Synthesis of2-(5-(benzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)-1H-indole(16k)

Prepared according to the General Procedure 2C from compound 15k (590mg, 1.04 mmol) and benzyl bromide (125 μL, 1.04 mmol) to afford 210 mg(31%) of 16k as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s,1H), 7.44-7.38 (m, 2H), 7.34-7.28 (m, 12H) 7.25-7.14 (m 4H), 7.04-6.96(m, 7H), 6.76 (s, 1H), 6.62 (s, 1H), 4.40 (s, 2H), 4.00 (m, 2H), 2.46(m, 2H), 1.82 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.95, 150.19,142.20, 139.16, 137.85, 137.15, 133.11, 132.45, 129.19, 128.99, 128.58,128.50, 128.10, 127.90, 127.66, 127.53, 127.40, 126.83, 125.39, 124.57,117.97, 74.28, 43.82, 28.81, 24.50.

Synthesis of3-((5-(Benzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-5-fluoro-1H-indole(161)

Prepared according to General Procedure 2C from cyclized compound 151(460 mg, 0.77 mmol) and benzyl bromide (92 μL, 0.77 mmol) to afford 460mg (87%) of the desired product 161 as a yellow foam: ¹H NMR (400 MHz,DMSO-d₆) δ 11.05 (s, 1H), 7.41-7.36 (m, 10H), 7.30-7.21 (m, 1H),7.23-7.20 (m, 2H), 7.15-7.04 (m, 11H), 6.91-6.85 (m, 1H), 6.56 (s, 1H),4.26 (s, 2H), 4.15 (s, 2H), 3.61 (d, J=7.6 Hz, 2H), 2.27 (d, J=6.9 Hz,2H), 1.46 (m, 2H). ¹³H NMR (100 MHz, DMSO-d₆) δ 157.74, 155.44, 154.41,148.39, 142.22, 139.22, 137.66, 137.21, 132.93, 129.18, 128.73, 128.31,128.21, 127.99, 127.33, 127.02 (d), 125.71, 117.65, 112.49 (d), 109.47(d), 108.73 (d), 103.35 (d), 74.51, 42.66, 37.60, 28.63, 24.44, 21.48,20.78.

Synthesis of3-((5-(3-Methoxybenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(21 g

Prepared according to General Procedure 2C from cyclized compound 15g(500 mg, 0.86 mmol) and 3-methoxybenzyl bromide (121 μL, 0.86 mmol) toafford 441 mg (73%) of 21 g as a yellow foam: ¹H NMR (400 MHz, DMSO-d₆)δ 10.93 (s, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.39-7.34 (m, 9H), 7.29 (d,J=8.2 Hz, 1H), 7.23 (d, J=1.4 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H), 7.05-7.00(m, 8H), 6.90 (m, 1H), 6.82 (m, 1H), 6.74-6.71 (m, 2H), 6.52 (s, 1H),4.25 (s, 2H), 4.17 (s, 2H), 3.65 (m, 2H), 3.62 (s, 3H), 2.25 (m, 2H),1.47 (m, 2H). ¹³H NMR (100 MHz, DMSO-d₆) δ 159.16, 154.57, 148.37,142.31, 139.53, 138.66, 137.71, 136.24, 129.40, 129.17, 128.16, 127.92,126.71, 123.57, 121.17, 120.93, 118.47, 117.55, 114.22, 113.04, 111.43,108.46, 74.36, 54.92, 42.74, 37.35, 28.75, 24.60, 21.60.

Synthesis of3-((5-(3-Methylbenzylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-JH-indole(22 g

Prepared according to General Procedure 2C from cyclized compound 15g(513 mg, 0.88 mmol) and 3-methylbenzyl bromide (119 μL, 0.88 mmol) toafford 485 mg (80%) of 22 g as a yellow foam: ¹H NMR (400 MHz, DMSO-d₆)δ 10.93 (s, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.40-7.36 (m, 9H), 7.29 (d,J=8.2 Hz, 1H), 7.22 (d, J=1.4 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H), 7.05-6.90(m, 12H), 6.52 (s, 1H), 4.23 (s, 2H), 4.17 (s, 2H), 3.65 (t, J=7.6 Hz,2H), 2.27 (t, J=6.9 Hz, 2H), 2.13 (s, 3H), 1.45 (m, 2H). ¹³H NMR (100MHz, DMSO-d₆) δ 154.54, 148.41, 142.31, 139.56, 137.70, 137.56, 137.00,136.25, 129.34, 129.17, 128.25, 128.16, 128.01, 127.92, 126.71, 125.84,123.55, 121.17, 118.47, 117.53, 111.43, 108.46, 74.35, 42.71, 37.49,28.72, 24.62, 20.79.

Synthesis of3-(2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(benzylthio)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(AH-1-47)

Prepared according to the General Procedure 2E from trityl protected 16a(218 mg g, 0.32 mmol) to afford 69 mg (49%) of AH-1-47 as a pale yellowsolid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (bs, 1H), 10.83 (bs, 1H), 7.48(s, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.29-7.24 (m,5H), 7.14 (d, J=1.8 Hz, 1H), 7.08 (t, J=7.3 Hz, 1H), 6.99 (t, J=7.3 Hz,1H), 6.76 (s, 1H), 4.31 (s, 2H), 3.65 (m, 2H), 3.10-2.97 (m, 4H), 1.72(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 155.47, 148.09, 137.26, 136.19,134.69, 128.91, 128.47, 127.45, 126.92, 122.65, 120.97, 118.32, 118.15,113.16, 111.38, 42.68, 37.45, 29.25, 25.55, 22.68. LCMS (05-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=6.53 minutes,ESI m/z=443.42 [M+H]⁺. HRMS (ESI+): m/z calculated for C₂₅H₂₇N₆S(M+H)+443.2012, found 443.2000.

Synthesis of3-(2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(3-chlorobenzylthio)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(AH-1-33)

Prepared according to the General Procedure 2E from 17a (320 mg g, 0.44mmol) to give 80 mg (38%) of AH-1-33 as a white solid: H NMR (400 MHz,DMSO-d₆) δ 10.81 (s, 1H), 7.47-7.42 (m, 2H), 7.36-7.23 (m, 5H), 7.13 (d,J=2.3 Hz, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.96 (t, J=7.8 Hz, 1H), 6.70 (s,1H), 4.30 (s, 2H), 3.66 (m, 2H), 3.08-3.04 (m, 2H), 2.99-2.95 (m, 2H),2.37 (m, 2H), 1.71 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 156.12, 148.37,140.64, 136.70, 135.21, 133.39, 130.80, 129.23, 128.15, 127.87, 127.41,123.15, 121.48, 118.84, 118.64, 113.68, 111.90, 43.17, 36.94, 29.64,26.02, 23.17. LCMS (25-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=5.83 minutes, ESI m/z=477.34 [M+H]⁺. HRMS (ESI+): m/zcalculated for C₂₅H₂₆C₁N₆S (M+H)+477.1623, found 477.1633.

Synthesis of3-(2-(4-(3-(1H-imidazol-4-yl)propyl-5-(3-fluorobenzylthio)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(AH-1-40)

Prepared according to the General Procedure 2E from 18a (250 mg, 0.36mmol) to afford 80 mg (49%) of AH-1-40 as a white solid: ¹H NMR (400MHz, DMSO-d₆) δ 10.82 (s, 1H), 7.47 (s, 1H), 7.44 (d, J=7.8 Hz, 1H),7.33-7.28 (m, 2H), 7.16-7.03 (m, 5H), 6.97 (t, J=7.3 Hz, 1H), 6.70 (s,1H), 4.32 (s, 2H), 3.67 (m, 2H), 3.07 (m, 2H), 2.98 (m, 2H), 2.37 (m,2H), 1.71 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) J 156.10, 148.89, 140.89(d), 136.71, 135.21, 130.92 (d), 127.42, 125.57, 125.54, 123.15, 121.47,118.83 (d), 116.28 (d), 116.28 (d), 114.87 (d), 113.67, 111.90, 43.18,37.04, 32.83, 29.64, 26.06, 23.18. LCMS (15-95% acetonitrile in 0.05%TFA over 10 minutes) retention time=6.27 minutes, ESI m/z=461.39 [M+H]⁺.HRMS (ESI+): m/z calculated for C₂₅H₂₆FN₆S (M+H)+461.1918, found461.1935.

Synthesis of3-(2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(3,4-dichlorobenzylthio)-4H-1,2,4-triazol-3-yl)ethyl)-1H-indole(AH-1-41)

Prepared according to the General Procedure 2E from compound 19a (450 mgg, 0.60 mmol) to afford 223 mg (73%) of AH-1-41 as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 7.57 (s, 1H), 7.53-7.43 (m, 3H),7.34-7.24 (m, 2H), 7.13 (s, 1H), 7.05 (m, 1H), 6.95 (m, 1H), 6.71 (s,1H), 4.31 (s, 2H), 3.69 (m, 2H), 3.05 (m, 2H), 2.98 (m, 2H), 2.37 (m,2H), 1.72 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 155.67, 147.71, 139.00,136.20, 134.71, 130.88, 130.81, 130.55, 129.98, 129.30, 127.78, 127.55,126.91, 122.64, 120.97, 118.32, 118.15, 113.17, 111.40, 42.71, 35.68,29.16, 25.56, 22.64. LCMS (15-95% acetonitrile in 0.05% TFA over 10minutes) retention time=6.60 minutes, ESI m/z=511.30 [M+H]⁺. HRMS(ESI+): m/z calculated for C₂₅H₂₅C₁₂N₆S (M+H)+511.1233, found 511.1246.

Synthesis of2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(benzylthio)-4H-1,2,4-triazol-3-yl)quinoline(AH-1-84)

Prepared according to the General Procedure 2E from compound 16b (310mg, 0.46 mmol) to give 49 mg (25%) of AH-1-84 as a yellow solid: ¹H NMR(400 MHz, DMSO-d₆) δ 8.53 (d, J=8.2 Hz, 1H), 8.30 (d, J=8.7 Hz, 1H),8.05 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.84-7.80 (m, 1H),7.69-7.65 (m, 1H), 7.46-7.39 (m, 2H), 7.33-7.18 (m, 5H), 6.72 (s, 1H),4.56 (m, 2H), 4.51 (s, 2H), 2.57 (m, 2H), 1.99 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆) δ 171.70, 142.38, 140.66, 137.65, 136.27, 129.24, 128.22,127.96, 126.95, 122.23, 120.98, 118.31, 118.22, 117.53, 113.49, 111.38,74.39, 43.32, 34.14, 28.40, 25.17, 20.39. IRMS (ESI+): m/z calculatedfor C₂₄H₂₃N₆S (M+H)+427.1693, found 427.1699.

Synthesis of2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(2-(1H-indol-3-yl)ethylthio)-4H-1,2,4-triazol-3-yl)quinoline(AH.2.132)

Prepared according to the General Procedure 2E from compound 17b (400mg, 0.55 mmol) to yield 31.2 mg (12%) of AH.2.132 as a yellow solid: ¹HNMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H), 8.53 (d, J=8.7 Hz, 1H), 8.32 (d,J=8.7 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.85 (m,2H), 7.71-7.64 (m, 2H), 7.50 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.25 (d,J=2.3 Hz, 1H), 7.08 (m, 1H), 7.00 (m, 1H), 4.65 (s, 2H), 3.59 (m, 2H),3.18 (m, 4H), 2.11 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 171.70, 142.38,140.66, 137.65, 136.27, 129.24, 128.22, 127.96, 126.95, 122.23, 120.98,118.31, 118.22, 117.53, 113.49, 111.38, 74.39, 43.32, 34.14, 28.40,25.17, 20.39. HRMS (ESI+): m/z calculated for C₂₄H₂₃N₆S(M+H)+427.169345, found 427.169942.

Synthesis of2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(3-bromobenzylthio)-4H-1,2,4-triazol-3-yl)quinoline(AH.2.160)

Prepared according to General Procedure 2E from derivative 18b (265 mg,0.35 mmol)) product AH.2.160 as a white foam (74 mg, 41%): ¹H NMR (400MHz, DMSO-d₆) δ 11.84 (s, 1H), 11.73 (s, 1H), 8.54 (d, J=8.7 Hz, 1H),8.31 (d, J=8.7 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.93 (m, 1H), 7.85 (t,J=6.8 Hz, 1H), 7.70 (d, J=6.8 Hz, 1H), 7.64 (s, 2H), 7.48-7.42 (m, 3H),7.28 (m, 1H), 6.81 (s, 1H), 4.58 (m, 2H), 4.52 (s, 2H), 2.55 (m, 2H),2.01 (m, 2H). 13H NMR (100 MHz, DMSO-d₆) δ 152.43, 152.09, 147.15,146.58, 140.24, 137.43, 134.66, 131.71, 130.63, 130.42, 130.35, 129.13,128.12, 127.99, 127.64, 127.38, 121.53, 119.90, 45.63, 35.79, 29.58.HRMS (ESI+): m/z calculated for C₃₇H₃₅N₆S (M+H)+595.2630, found595.2638.

Synthesis of4-(3-(1H-imidazol-4-yl)propyl)-3-(benzylthio)-5-(naphthalen-2-yl)-4H-1,2,4-triazole(AH-1-75)

Prepared according the General Procedure 2E from 16c (226 mg, 0.34 mmol)to afford 24 mg (32% yield) of AH-1-75 as a white solid: ¹H NMR (400MHz, DMSO-d₆) δ 8.12 (s, 1H), 8.01-7.95 (m, 3H), 7.67-7.65 (m, 1H),7.59-7.57 (m, 2H), 7.39-7.16 (m, 6H), 6.63 (s, 1H), 6.41 (s, 1H), 4.41(s, 2H), 3.93 (m, 2H), 2.27 (m, 2H), 1.75 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 171.70, 142.38, 140.66, 137.65, 136.27, 129.24, 128.22,127.96, 126.95, 122.23, 120.98, 118.31, 118.22, 117.53, 113.49, 111.38,74.39, 43.32, 34.14, 28.40, 25.17, 20.39. HRMS (ESI+): m/z calculatedfor C₂₅H₂₄N₅S (M+H)+426.1747, found 426.1747.

Synthesis of4-(3-(1H-imidazol-4-yl)propyl)-3-(benzylthio)-5-phenethyl-4H-1,2,4-triazole(AH-1-81)

Prepared according to the General Procedure 2E from 16d (300 mg, 0.46mmol) to yield 83 mg (44%) of AH-1-81 as a white solid: ¹H NMR (400 MHz,DMSO-d₆) δ 11.73 (s, 1H), 7.46 (s, 1H), 7.23-7.13 (m, 10H), 6.75 (s,1H), 4.27 (s, 1H), 3.65 (m, 2H), 2.92-2.85 (m, 4H), 2.34 (m, 2H), 1.69(m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 155.05, 148.30, 140.69, 137.32,134.81, 128.95, 128.54, 128.49, 128.41, 127.55, 126.24, 42.62, 37.46,32.60, 29.13, 26.29. HRMS (ESI+): m/z calculated for C₂₃H₂₆N₅S(M+H)+404.1910, found 404.1903.

Synthesis of3-(4-(3-(1H-imidazol-4-yl)propyl)-5-(benzylthio)-4H-1,2,4-triazol-3-yl)-1H-indole(AH-1-86)

Prepared according to the General Procedure 2E from compound 16e (390mg, 0.6 mmol) to yield 154 mg (63%) of AH-1-86 as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 11.67 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.71 (s,1H), 7.51 (s, 1H), 7.48-7.46 (d, J=7.8 Hz, 1H), 7.36-7.25 (m, 4H), 7.20(t, J=8.2 Hz, 1H), 7.12 (t, J=8.3 Hz, 1H), 6.67 (s, 1H), 4.40 (s, 2H),3.94 (m, 2H), 2.43 (m, 2H), 1.81 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ151.16, 148.37, 137.55, 135.93, 134.82, 129.01, 128.53, 127.52, 125.75,125.02, 122.39, 120.91, 120.27, 111.85, 101.79, 43.63, 37.64, 28.89.HRMS (ESI+): m/z calculated for C₂₃H₂₃N₆S (M+H)+415.1699, found415.1699.

Synthesis of4-(3-(1H-imidazol-4-yl)propyl)-3-(benzylthio)-5-phenyl-4H-1,2,4-triazole(AH-1-96)

Prepared according to the General Procedure 2E from 16f (400 mg, 0.65mmol) to afford 113 mg (47%) of compound AH-1-96 as a white solid: ¹HNMR (400 MHz, DMSO-d₆) δ 7.51-7.44 (m, 6H), 7.32-7.14 (m, 8H), 4.38 (s,2H), 3.79 (m, 2H), 2.25 (m, 2H), 1.70 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 155.05, 150.10, 147.85, 137.20, 134.86, 130.11, 129.09,129.05, 128.61, 128.41, 127.86, 127.65, 127.27, 126.76, 48.71, 43.79,37.42, 29.14. HRMS (ESI+): m/z calculated for C₂₁H₂₂N₅S (M+H)+376.1557,found 376.1590.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(benzylthio)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(AH-1-94)

Prepared according to the General Procedure 2E from compound 16g (605mg, 0.9 mmol) to afford 305 mg (79%) of AH-1-94 as a yellow solid: ¹HNMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 10.94 (s, 1H), 7.50 (s, 1H),7.46 (d, J=7.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.16-7.04 (m, 7H), 6.94(t, J=7.8 Hz, 1H), 6.69 (s, 1H), 4.25 (s, 2H), 4.15 (s, 2H), 3.58 (m,2H), 2.28 (m, 2H), 1.54 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.70,148.56, 137.34, 136.41, 134.81, 128.83, 128.48, 127.45, 126.81, 123.68,118.65, 111.59, 108.36, 42.78, 37.88, 29.01, 23.54, 21.82. HRMS (ESI+):m/z calculated for C₂₄H₂₅N₆S (M+H)+429.1886, found 429, 1856.

Synthesis of34(44341H-imidazol-4-yl)propyl)-5-(3-(trifluoromethyl)benzylthio)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(AH.1.109)

Prepared according to the General Procedure 2E from compound 17g (400mg, 0.54 mmol) to afford 106 mg (44%) of AH.1.109 as a white foam: ¹HNMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H), 10.96 (s, 1H), 7.70 (s, 1H),7.55-7.43 (m, 4H), 7.35-7.32 (m, 2H), 7.08-7.04 (m, 2H), 6.94 (m, 1H),6.69 (s, 1H), 4.41 (s, 2H), 4.16 (s, 2H), 3.66 (m, 2H), 2.30 (m, 2H),1.53 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.73, 148.08, 139.19,136.30, 134.69, 132.93, 129.36, 126.71, 125.48, 124.02, 123.57, 121.23,118.53, 111.49, 108.28, 42.77, 36.46, 28.93, 21.67. HRMS (ESI+): m/zcalculated for C₂₅H₂₄F₃N₆S (M+H)+497.1764, found 497.1730.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3-fluorobenzylthio)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(AH.1.118)

Prepared according to the General Procedure 2E from compound 18g (500mg, 0.73 mmol) to give 151 mg (47%) of AH.1.118 as a yellow foam: ¹H NMR(400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 10.94 (s, 1H), 7.49 (s, 1H), 7.42(d, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.15-6.91 (m, 7H), 6.69 (s,1H), 4.30 (s, 2H), 4.16 (s, 2H), 3.66 (m, 2H), 2.28 (m, 2H), 1.55 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 163.16, 160.74, 154.73, 148.27,140.36, 140.28, 136.33, 134.72, 130.32 (d), 126.73, 124.93, 123.59,121.27, 118.58 (d), 115.74 (d), 114.35 (d), 111.52, 108.34, 42.81,36.70, 28.97, 21.72. HRMS (ESI+): m/z calculated for C₂₄H₂₄FN₆S(M+H)+447.1747, found 447.1762.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3,4-dichlorobenzylthio)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(AH.1.116)

Prepared according to the General Procedure 2E from 19 g (412 mg, 0.56mmol) to afford 153 mg (41%) of compound AH.1.116 as a yellow foam: ¹HNMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H), 10.95 (s, 1H), 7.57 (s, 1H),7.51 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.27 (d,J=8.2 Hz, 1H), 7.11-7.10 (m, 2H), 7.06 (t, J=7.8 Hz, 1H), 6.93 (t, J=7.7Hz, 1H), 6.69 (s, 1H), 4.28 (s, 2H), 4.17 (s, 2H), 3.67 (m, 2H), 2.29(m, 2H), 1.54 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.78, 148.03,138.96, 136.31, 134.68, 130.82, 130.38, 129.95, 129.06, 127.79, 127.55,126.72, 123.60, 121.23, 118.55, 111.51, 108.26, 42.79, 35.83, 28.93,21.72. HRMS (ESI+): m/z calculated for C₂₄H₂₃C₁₂N₆S (M+H)+497.1077,found 497.1076.

169

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3-bromobenzylthio)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(AH. 1.112)

Prepared according to the General Procedure 2E from compound 20g (440mg, 0.59 mmol) to yield 261 mg (88%) of AH.1.112 as a white solid: ¹HNMR (400 MHz, DMSO-d₆) δ 11.73 (s, 1H), 10.93 (s, 1H), 7.505-7.30 (m,5H), 7.15 (m, 1H), 7.07-7.03 (m, 3H), 6.93 (m, 1H), 6.69 (s, 1H), 4.28(s, 2H), 4.15 (s, 2H), 3.66 (m, 2H), 2.28 (m, 2H), 1.54 (m, 2H). ¹³C NMR(100 MHz, DMSO-d₆) δ 154.81, 148.30, 136.38, 134.78, 131.63, 130.54,130.27, 127.93, 126.78, 123.64, 121.56 (d), 118.67 (d), 111.58, 108.37,42.87, 36.56, 28.99, 21.75. HRMS (ESI+): m/z calculated for C₂₄H₂₄BrN₆S(M+H)+507.0956, found 507.0961.

Synthesis of4-(3-(1H-imidazol-4-yl)propyl)-3-(benzylthio)-5-(naphthalen-1-yl)-4H-1,2,4-triazole(AH.1.102)

Prepared according to the General Procedure 2E from compound 16h (264mg, 0.40 mmol) to afford 77 mg (46%) of AH.1.102 as a white foam: ¹H NMR(400 MHz, DMSO-d₆) δ 11.56 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.00 (d,J=7.8 Hz, 1H), 7.61-7.50 (m, 4H), 7.31-7.24 (m, 7H), 6.32 (s, 1H), 4.39(s, 2H), 3.49 (m, 2H), 2.03 (m, 2H), 1.46 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 153.76, 149.41, 137.35, 134.62, 133.12, 131.44, 130.66,129.08, 128.81, 128.63, 127.63, 127.46, 126.72, 125.42, 124.63, 124.55,43.66, 38.12, 29.15. HRMS (ESI+): m/z calculated for C₂₅H₂₃N₅S(M+H)+426.1774, found 426.1747.

Synthesis of2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(benzylthio)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole(AH.2.126)

Prepared according to the General Procedure 2E from 16i (123 mg, 0.18mmol) to give 26 mg (33%) of compound AH.2.126 as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 9.04 (s, 1H), 7.47-7.25 (m, 8H),7.07 (m, 1H), 6.81 (s, 1H), 4.46 (s, 2H), 4.09 (m, 2H), 2.68 (m, 2H),1.93 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 171.70, 142.38, 140.66,137.65, 136.27, 129.24, 128.22, 127.96, 126.95, 122.23, 120.98, 118.31,118.22, 117.53, 113.49, 111.38, 74.39, 43.32, 34.14, 28.40, 25.17,20.39. HRMS (ESI+): m/z calculated for C₂₄H₂₃N₆S (M+H)+427.169345, found427.169942.

Synthesis of4-(3-(1H-imidazol-4-yl)propyl)-3-(benzylthio)-5-(4-fluorophenethyl)-4H-1,2,4-triazole(AH.2.130)

Prepared according to the General Procedure 2E from compound 16j (585mg, 0.88 mmol) to afford 84 mg (23% yield) of AH.2.130 as a white solid:¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (m, 2H), 7.47-7.42 (m, 3H) 7.37-7.19 (m15H), 7.04-7.00 (m, 6H), 6.48 (s, 1H), 4.41 (s, 2H), 3.81 (t, J=7.8 Hz,2H), 2.30 (t, J=6.8 Hz, 2H), 1.70 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ154.95, 150.19, 142.20, 139.16, 137.85, 137.15, 133.11, 132.45, 129.19,128.99, 128.58, 128.50, 128.10, 127.90, 127.66, 127.53, 127.40, 126.83,125.39, 124.57, 117.97, 74.28, 43.82, 28.81, 24.50. HRMS (ESI+): m/zcalculated for C₂₄H₂₃N₆S (M+H)+427.169345, found 427.169942.

Synthesis of2-(4-(3-(1H-imidazol-4-yl)propyl)-5-(benzylthio)-4H-1,2,4-triazol-3-yl)-1H-indole(AH.2.131)

Prepared according to the General Procedure 2E from 16k (150 mg, 0.23mmol) to yield 47.2 mg (50%) of compound AH.2.131 as a white solid: ¹HNMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.73 (s, 1H), 7.57 (d, J=7.8 Hz,1H), 7.43 (d, J=8.2 Hz, 1H), 7.37-7.24 (m, 5H), 7.21-7.16 (m, 2H), 7.05(m, 1H), 6.85 (s, 1H), 6.62 (d, J=1.8 Hz, 1H), 4.44 (s, 2H), 4.08 (m,2H), 2.55 (m, 2H), 1.87 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ171.70,142.38, 140.66, 137.65, 136.27, 129.24, 128.22, 127.96, 126.95, 122.23,120.98, 118.31, 118.22, 117.53, 113.49, 111.38, 74.39, 43.32, 34.14,28.40, 25.17, 20.39. LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=2.10 minutes, ESI m/z=415.40 [M+H]⁺. HRMS(ESI+): m/z calculated for C₂₄H₂₃N₆S (M+H)+427.169345, found 427.169942.

Synthesis of3-((4-(3-(1H-Imidazol-4-yl)propyl)-5-(benzylthio)-4H-1,2,4-triazol-3-yl)methyl)-5-fluoro-1H-indole(AH.2.145)

Prepared according to General Procedure 2E from derivative 161 (400 mg,0.58 mmol)) product AH.2.145 as a yellow foam (57 mg, 21%): ¹H NMR (400MHz, DMSO-d₆) δ 11.97 (s, 1H), 11.08 (s, 1H), 7.52 (s, 1H), 7.36-7.32(m, 1H), 7.23-7.12 (m, 6H), 6.92 (m, 2H), 6.72 (s, 1H), 4.27 (s, 2H),4.15 (s, 2H), 3.62 (m, 2H), 2.30 (m, 2H), 1.55 (m, 2H). ¹³H NMR (100MHz, DMSO-d₆) δ 157.75, 155.46, 154.42, 148.46, 137.28, 134.68, 133.00,128.77, 128.35, 127.36, 127.01 (d), 125.69, 112.55 (d), 109.52 (d),108.63, 103.36 (d), 42.68, 37.69, 21.56. HRMS (ESI+): m/z calculated forC₂₄H₂₄FN₆S (M+H)+447.1762, found 447.1787.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3-methoxybenzylthio)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(AH.2.162)

Prepared according to General Procedure 2E from derivative AH-1-94 (441mg, 0.63 mmol)) product AH.2.162 as a yellow foam (151 mg, 53%): ¹H NMR(400 MHz, DMSO-d₆) δ 11.76 (s, 1H), 10.95 (s, 1H), 7.51-7.46 (m, 2H),7.35 (d, J=8.2 Hz, 1H), 7.08-7.02 (m, 3H), 6.97 (t, J=7.8 Hz, 1H), 6.85(s, 1H), 6.77-6.70 (m, 3H), 4.27 (s, 2H), 4.17 (s, 2H), 3.65 (m, 5H),2.31 (m, 2H), 1.56 (m, 2H). 13H NMR (100 MHz, DMSO-d₆) δ 159.18, 154.57,148.44, 138.74, 136.29, 134.64, 129.43, 126.72, 123.52, 121.22, 120.95,118.53, 114.22, 113.06, 111.46, 108.37, 54.93, 42.78, 37.45, 28.96,24.57, 21.66. HRMS (ESI+): m/z calculated for C₃₇H₃₅N₆S (M+H)+595.2630,found 595.2638.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3-methylbenzylthio)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(AH.2.165)

Prepared according to General Procedure 2E from derivative AH.1.109 (421mg, 0.61 mmol)) to yield AH.2.165 as a yellow foam (139 mg, 51%): ¹H NMR(400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 10.94 (s, 1H), 7.50-7.45 (m, 2H),7.37-7.18 (m, 2H), 7.07-6.92 (m, 6H), 6.69 (s, 1H), 4.23 (s, 2H), 4.16(s, 2H), 3.64 (m, 2H), 2.30 (m, 2H), 2.17 (s, 3H), 1.54 (m, 2H). ¹³H NMR(100 MHz, DMSO-d₆) δ 157.75, 155.46, 154.42, 148.46, 137.28, 134.68,133.00, 128.77, 128.35, 127.36, 127.01 (d), 125.69, 112.55 (d), 109.52(d), 108.63, 103.36 (d), 42.68, 37.69, 21.56. HRMS (ESI+): m/zcalculated for C₃₇H₃₅N₆S (M+H)+595.2630, found 595.2638.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(4-bromobenzylthio)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(MS.1.22)

Prepared according to General Procedure E from derivative 19o (491 mg,0.65 mmol) to give product MS.1.22 as a yellow foam (169 mg, 51%): ¹HNMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 10.95 (s, 1H), 7.50 (s, 1H),7.45 (d, J=8 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.30-7.17 (m, 3H),7.10-7.04 (m, 4H), 6.94 (m, 1H), 4.21 (s, 2H), 4.16 (s, 2H), 3.59 (m,2H), 2.28 (m, 2H), 1.53 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.69,148.16, 147.78, 136.98, 136.33, 134.68, 131.21, 130.88, 128.14, 127.90,127.79, 127.55, 126.73, 126.67, 123.61, 121.21, 120.52, 118.54, 111.55,108.21, 42.65, 36.89, 28.90, 21.79. IRMS (ESI+): m/z calculated forC₂₄H₂₄BrN₆S (M+H)⁺ 507.0961, found 507.0974.

Synthesis of Methyl4-((4-(3-(1H-imidazol-4-yl)propyl)-5-((1H-indol-3-yl)methyl)-4H-1,2,4-triazol-3-ylthio)methyl)benzoate(MS.1.27)

Prepared according to General Procedure E from derivative 20o (395 mg,0.54 mmol)) to yield MS.1.27 as a yellow foam (164 mg, 62%): ¹H NMR (400MHz, DMSO-d₆) δ 11.76 (s, 1H), 10.95 (s, 1H), 7.69-7.67 (m, 2H), 7.50(s, 1H), 7.45 (m, 1H), 7.35-7.28 (m, 3H), 7.11-7.05 (m, 2H), 6.95 (m,1H), 6.67 (bs, 1H), 4.34 (s, 2H), 4.17 (s, 2H), 3.8 (s, 3H), 3.60 (m,2H), 2.29 (m, 2H), 1.53 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 165.90,154.73, 148.08, 143.09, 136.32, 134.64, 129.24, 129.05, 128.51, 126.70,123.59, 121.22, 118.51, 111.51, 108.20, 52.11, 42.69, 37.17, 28.90,21.78. HRMS (ESI+): m/z calculated for C₂₆H₂₇N₆O₂S (M+H)⁺ 487.1911,found 487.1924.

Synthesis of4-(3-(1H-imidazol-4-yl)propyl)-3-(3-methoxybenzylthio)-5-phenethyl-4H-1,2,4-triazole(MS.1.30)

Prepared according to General Procedure E from derivative 17d (441 mg,0.63 mmol) to give product MS.1.30 as a yellow foam: H NMR (400 MHz,DMSO-d₆) δ 7.48 (s, 1H), 7.28-7.16 (m, 7H), 6.85-6.80 (m, 7H), 6.85-6.79(m, 4H), 4.28 (s, 2H), 3.68 (m, 5H), 2.96-2.90 (m, 4H), 2.39 (m, 2H),1.71 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.18, 154.57, 148.44,138.74, 136.29, 134.64, 129.43, 126.72, 123.52, 121.22, 120.95, 118.53,114.22, 113.06, 111.46, 108.37, 54.93, 42.78, 37.45, 28.96, 24.57,21.66. HRMS (ESI+): m/z calculated for C₂₄H₂₈N₅OS (M+H)⁺ 434.2009, found434.2009.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(3-methylbenzylthio)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(AH2.182)

Prepared according to General Procedure E from derivative 17m (445 mg,0.63 mmol) to afford product AH.2.182 as a yellow foam (129 mg, 44%): ¹HNMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H), 11.03 (s, 1H), 7.51 (s, 1H),7.45 (m, 1H), 7.13-6.95 (m, 7H), 6.81 (m, 1H), 4.25 (s, 2H), 4.16 (s,2H), 3.65 (m, 2H), 2.31 (m, 2H), 1.55 (m, 2H). ¹³C NMR (100 MHz,DMSO-d₆) δ 160.16, 157.83, 154.50, 148.65, 137.71, 137.11, 136.30 (d),134.75, 129.43, 128.33 (d), 127.84 (d), 126.74, 125.91, 124.24 (d),123.65, 119.70 (d), 108.73, 107.28 (d), 97.62 (d), 42.81, 37.68, 28.95,21.62, 20.96. HRMS (ESI+): m/z calculated for C₂₅H₂₆FN₆S (M+H)+461.1918,found 461.1926.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(benzylthio)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(AH.2.178)

Prepared according to General Procedure E from derivative 16m (405 mg,0.59 mmol) to give product AH.2.178 as a yellow foam (112 mg, 43%): ¹HNMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H), 11.03 (s, 1H), 7.52 (s, 1H),7.44 (m, 1H), 7.32-7.08 (m, 7H), 6.84 (m, 1H), 6.71 (s, 1H), 4.27 (s,2H), 4.16 (s, 2H), 3.61 (m, 2H), 2.30 (m, 2H), 1.54 (m, 2H). ¹³C NMR(100 MHz, DMSO-d₆) δ 160.11, 157.78, 154.46, 148.47, 147.79, 137.28,136.26 (d), 134.72, 128.78, 128.37, 127.80, 127.56, 127.37, 126.67,124.20 (d), 123.61, 119.66 (d), 108.64, 107.21 (d), 97.58 (d), 42.68,37.72, 28.94, 21.64. HRMS (ESI+): m/z calculated for C₂₄H₂₄FN₆S(M+H)+447.1762, found 447.1757.

Synthesis of4-(3-(1H-imidazol-4-yl)propyl)-3-benzyl-5-(benzylthio)-4H-1,2,4-triazole(AH.2.199)

Prepared according to General Procedure E from derivative 17n (200 mg,0.32 mmol) to afford product AH.2.199 as a white solid (72 mg, 59%): ¹HNMR (400 MHz, DMSO-d₆) δ 11.78 (s, 1H), 7.53 (s, 1H), 7.32-7.28 (m, 2H),7.25-7.19 (m, 6H), 7.10 (m, 1H), 4.30 (s, 2H), 4.08 (s, 2H), 3.59 (m,2H), 2.33 (m, 2H), 1.57 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 154.35,148.67, 137.24, 136.17, 134.69, 128.83, 128.61, 128.44, 128.40, 127.42,126.78, 42.74, 37.65, 30.44, 28.92. HRMS (ESI+): m/z calculated forC₂₅H₂₆FN₆S (M+H)⁺ 461.1918, found 461.1926.

Synthesis of4-(3-(1H-imidazol-4-yl)propyl)-3-benzyl-5-(benzylthio)-4H-1,2,4-triazole(AH.2.206)

Prepared according to General Procedure E from derivative 18n (200 mg,0.30 mmol) to afford product AH.2.206 as a white solid (39 mg, 31%): ¹HNMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 7.51 (s, 1H), 7.30-7.08 (m, 6H),6.83-6.71 (m, 3H), 4.27 (s, 2H), 4.07 (s, 2H), 3.68 (s, 3H), 3.65 (m,2H), 2.31 (m, 2H), 1.55 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.19,154.34, 148.71, 138.73, 136.18, 134.69, 129.50, 128.60, 128.39, 126.77,121.00, 114.27, 113.07, 54.98, 42.82, 37.51, 30.44, 28.93. HRMS (ESI+):m/z calculated for C₂₅H₂₆FN₆S (M+H)⁺ 461.1918, found 461.1926.

General Procedure 2F: General Thiol Cross Coupling (to be Inserted afterGeneral Procedure 2E on page 89).

In the main reaction flask a mixture of cyclized derivative 15m-o (1mmol), Zn(OAc)₂ (2 mmol), sodium dithionite (Na₂SO₄, 2 mmol), sodiumt-butoxide (2.5 mmol), N-XantPhos (0.1 mmol) and Pd₂dba₃.CHCI₃ (0.05mmol) was subjected to 3 vacuum/argon purge cycles and left under argonflow. In a separate flask, a mixture of DMSO (15 mL) and the aryl halide(3-5 mmol) were sparged with dry Argon for 15 min and the mixture wastransferred to the main reaction flask with a pressurized cannula. Thereaction was heated at 90° C. for 16 hours thereafter. The mixture wascooled and partitioned with EtOAc (150 mL) and water (100 mL). Thelayers were separated and the EtOAc solution was washed with water (2×50mL) and brine (50 mL). The EtOAc layer was dried (Na₂SO₄), filtered andconcentrated to afford the desired aryl sulfide product.

Synthesis of6-fluoro-3-((5-((4-fluorophenyl)thio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(68a)

Prepared according to General Procedure 2F from5-((6-fluoro-1H-indol-3-yl)methyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15m) (216 mg, 0.36 mmol) and 1-fluoro-4-iodobenzene (208 μL, 400 mg,1.80 mmol) using Zn(OAc)² (99 mg, 0.54 mmol), sodium dithionite (125 mg,0.72 mmol), sodium t-butoxide (86 mg, 0.90 mmol), N-XantPhos (20 mg,0.036 mmol) and Pd₂dba₃.CHCI₃ (10 mg, 0.018 mmol) to afford 307 mg ofcompound 68a as an orange oil (this material was used in the next stepwithout further purification): ¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (bs,1H), 7.71 (dd, J=8.70, 5.10 Hz, 1H), 7.37-7.29 (complex overlapping m,10H), 7.23-7.20 (m, 2H), 7.16 (d, J=1.80 Hz, 1H), 7.07 (t, J=8.70 Hz,1H), 7.03-6.97 (m, 6H), 6.73 (dt, J=8.70, 2.30 Hz, 1H), 6.48 (bs, 1H),4.19 (s, 2H), 3.84 (apparent t, J˜7.00 Hz, 2H), 2.29 (t, J=6.90 Hz, 2H),1.49 (quint., J=7.00 Hz, 2H). LCMS (40-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=8.60 min, ESI m/z=693 [M+H]⁺.

Synthesis of6-fluoro-3-((5-(p-tolylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-JH-indole(68b)

Prepared according to General Procedure 2F from5-((6-fluoro-1H-indol-3-yl)methyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15m) (300 mg, 0.50 mmol) and 4-iodotoluene (545 mg, 2.50 mmol) usingZn(OAc)₂ (138 mg, 0.75 mmol), sodium dithionite (174 mg, 1.00 mmol),sodium t-butoxide (120 mg, 1.25 mmol), N-XantPhos (28 mg, 0.05 mmol) andPd₂dba₃.CHCI₃ (26 mg, 0.025 mmol). Purification by flash chromatography(SiO₂, 40:1 CH2CI2/MeOH to 20:1) afforded 247 mg (72% yield) of compound68b as a tan solid: ¹H NMR (400 MHz, DMSO-d₆, t=100° C.) δ 10.70 (bs,1H), 7.38-7.30 (complex overlapping m, 10H), 7.20 (bs, 1H), 7.11 (d,J=2.30 Hz, 1H), 7.08-7.02 (complex overlapping m, 11H), 7.01 (d, J=2.30Hz, 1H), 6.71 (dt, J=9.00, 2.30 Hz, 1H), 6.50 (bs, 1H), 4.18 (s, 2H),3.85 (apparent t, J˜7.30 Hz, 2H), 2.23 (t, J=7.30 Hz, 2H), 1.63 (quint.,J=7.80 Hz, 2H). LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes)retention time=5.55 min, ESI m/z=689 [M+H]⁺.

Synthesis of6-fluoro-3-((5-((3-methoxyphenvnthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(68c)

Prepared according to General Procedure 2F from5-((6-fluoro-1H-indol-3-yl)methyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15m) (300 mg, 0.50 mmol) and 3-bromoanisole (317 μl_, 468 mg, 2.50mmol) using Zn(OAc)₂ (138 mg, 0.75 mmol), sodium dithionite (174 mg,1.00 mmol), sodium t-butoxide (120 mg, 1.25 mmol), N-XantPhos (28 mg,0.05 mmol) and Pd₂dba₃.CHCI₃ (26 mg, 0.025 mmol). Purification by flashchromatography (SiO₂, 40:1 CH2CI2/MeOH to 20:1) afforded 264 mg (75%yield) of compound 68c as a tan solid: ¹H NMR (400 MHz, DMSO-d₆, t=25°C., peaks are broadened due to slow rotational interconversion) δ 10.96(bs, 1H), 7.38-7.28 (complex overlapping m, 10H), 7.17 (bs, 2H), 7.07(t, J=8.30 Hz, 1H), 7.03-6.97 (m, 7H), 6.74-6.67 (m, 2H), 6.58 (m, 2H),6.43 (s, 1H), 4.21 (s, 2H), 3.84-3.81 (m, 2H), 3.52 (s, 3H), 2.27-2.24(m, 2H), 1.51-1.43 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 160.21, 159.39(d, ¹J_(CF)=234 Hz), 156.35, 146. 13, 142.82, 140.08, 138.20, 136.62 (d,J_(CF)=4.40 Hz), 134.55, 130.93, 129.67, 128.69, 128.46, 124.87 (d,J_(CF)=2.90 Hz), 124.05, 120.09, 119.99 (d, J_(CF)=9.50 Hz), 117.98,113.71, 113.50, 109.00, 107.59 (d, J_(CF)=23.9 Hz), 97.95 (J_(CF)=24.9Hz), 74.85, 55.59, 43.93, 29.51, 25.19, 22.38. LCMS (50-95% acetonitrilein 0.05% TFA over 10 minutes) retention time=5.67 min, ESI m/z=705[M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-((4-fluorophenyl)thio)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-JH-indole(SK-I-128)

Prepared according to General Procedure 1D from6-fluoro-3-((4-fluorophenyl)thio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(68a) (270 mg, 0.39 mmol) and afforded 77 mg (44% yield) of compoundSK-I-128 as a white solid: ¹H NMR (400 MHz, DMSO-d₆, t=30° C., peaks arebroadened due to slow rotational interconversion and/or tautomericequilibration) δ 11.73 (bs, 1H), 11.00 (bs, 1H), 7.48 (bs, 1H), 7.36(apparent t, J˜6.90 Hz, 1H), 7.27-7.22 (m, 2H), 7.16-7.12 (m, 3H), 7.06(bd, J=10.0 Hz, 1H), 6.78 (bt, J=8.70 Hz, 1H), 6.64 (bs, 0.6H), 6.46(bs, 0.4H), 4.19 (s, 2H), 3.867-3.75 (bm, 2H), 2.38-2.25 (bm, 2H),1.54-1.46 (bm, 2H). LCMS (50-95% acetonitrile in 0.05% TFA over 10minutes) retention time=2.05 min, ESI m/z=451 [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(p-tolylthio)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(SK-I-130)

Prepared according to General Procedure 1D from6-fluoro-3-((5-(p-tolylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(68b) (162 mg, 0.24 mmol) and afforded 94 mg (88% yield) of compoundSK-I-130 as a white solid: ¹H NMR (400 MHz, DMSO-d₆, t=100° C., peaksare broadened due to slow rotational interconversion and/or tautomericequilibration) δ 11.43 (bs, 1H), 10.73 (bs, 1H), 7.41 (bs, 1H), 7.37(dd, J=8.70, 5.50 Hz, 1H), 7.12-7.06 (complex overlapping m, 5H), 7.04(d, J=2.30 Hz, 1H), 6.75 (dt, J=8.70, 2.30 Hz, 1H), 6.61 (bs, 0.6H),6.47 (bs, 0.4H), 4.19 (s, 2H), 3.89-3.81 (bm, 2H), 2.38-2.31 (bm, 2H),2.22 (s, 3H), 1.69-1.60 (bm, 2H). LCMS (50-95% acetonitrile in 0.05% TFAover 10 minutes) retention time=2.15 min, ESI m/z=447 [M+H]⁺.

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-((3-methoxyphenyl)thio)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(SK-I-132)

Prepared according to General Procedure 1 D from6-fluoro-3-((5-((3-methoxyphenyl)thio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(68c) (82 mg, 0.12 mmol) and afforded 49 mg (91% yield) of compoundSK-I-132 as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.51 (d, J=1.40 Hz,1H), 7.29 (dd, J=8.70, 5.50 Hz, 1H), 7.14 (t, J=7.80 Hz, 1H), 7.00 (dd,J=10.0, 2.30 Hz, 1H) 6.98 (s, 1H), 6.75 (dd, J=8.70, 2.30 Hz, 2H),6.71-6.67 (m, 1H), 6.64 (t, J=1.80 Hz, 1H), 6.55 (s, 1H), 4.30 (s, 2H),3.82-3.78 (m, 2H), 3.61 (s, 3H), 2.34 (t, J=7.40 Hz, 2H), 1.53 (quint.,J=7.80 Hz, 2H). ¹³C NMR (100 MHz, CD₃OD) δ 160.58, 159.99 (d,¹J_(CF)=235 Hz), 156.74, 148.15, 136.87 (d, J_(CF)=12.4 Hz), 134.64,132.64, 130.25, 123.67 (d, J_(CF)=2.90 Hz), 123.35, 120.83, 118.80 (d,J_(CF)=9.50 Hz), 114.03, 113.45, 107.90, 107.45 (d, J_(CF)=24.9 Hz),97.12 (d, J_(CF)=25.9 Hz), 54.44, 43.82, 28.86, 23.50 (broad), 22.08.LCMS (25-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=5.67 min, ESI m/z=463 [M+H]⁺.

Synthesis of6-fluoro-3-((5-(pyridin-3-ylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(BN-VII-95)

Prepared according to General Method 2F from5-((6-fluoro-1H-indol-3-yl)methyl)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole-3-thiol(15m) (300 mg, 0.50 mmol) and 3-iodopyridine (308 mg, 1.50 mmol) usingZn(OAc)₂ (138 mg, 0.75 mmol), sodium dithionite (174 mg, 1.00 mmol),sodium t-butoxide (120 mg, 1.25 mmol), N-XantPhos (28 mg, 0.05 mmol) andPd₂dba₃.CHCI₃ (26 mg, 0.025 mmol). Trituration of the isolated residuewith CH₂Cl₂ afforded ˜350 mg of crude compound BN-VII-95 as a tan solid:LCMS (50-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=3.38 min, ESI m/z=676 [M+H]⁺. This material was taken on to thenext step “as is.”

Synthesis of3-((4-(3-(1H-imidazol-4-yl)propyl)-5-(pyridin-3-ylthio)-4H-1,2,4-triazol-3-yl)methyl)-6-fluoro-1H-indole(BN-VII-97)

Prepared according to General Procedure 1D from6-fluoro-3-((5-(pyridin-3-ylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazol-3-yl)methyl)-1H-indole(BN-VII-95) (350 mg, <0.5 mmol) and afforded 97 mg (45% yield for twosteps) of compound BN-VII-97 as a colorless glass: ¹H NMR (400 MHz,CD₃OD) δ 8.43-8.41 (m, 2H), 7.69 (dd, J=2.30, 1.30 Hz, 1H), 7.67 (dd,J=2.30, 1.40 Hz, 1H), 7.54 (d, J=0.90 Hz, 1H), 7.34-7.32 (m, 1H), 7.30(dd, J=8.70, 5.50 Hz, 1H), 7.01 (dd, J=9.60, 2.30 Hz, 1H), 7.01 (s, 1H),6.77-6.72 (m, 1H), 6.60 (s, 1H), 4.31 (s, 2H), 3.89-3.85 (m, 2H), 2.38(t, J=7.30 Hz, 2H), 1.55 (quint., J=7.60 Hz, 2H). ¹³C NMR (100 MHz,CD₃OD) δ 159.97 (d, ¹J_(CF)=235.8 Hz), 156.76, 149.34, 148.34, 147.41,138.23, 136.83 (J_(CF)=12.4 Hz), 134.75, 129.86, 124.71, 123.74 (d,J_(CF)=2.90 Hz), 123.36, 118.76 (d, J_(CF)=9.60 Hz), 107.81, 107.46 (d,J_(CF)=24.9 Hz), 97.14 (d, J_(CF)=25.8 Hz), 43.84, 29.09, 23.58, 21.98.LCMS (15-95% acetonitrile in 0.05% TFA over 10 minutes) retentiontime=5.63 min, ESI m/z=434 [M+H]⁺.

Synthesis of4-(3-(1H-imidazol-4-yl)propyl)-3-(naphthalene-1-ylmethyl)-5-(phenylsulfonyl)-4H-1,2,4-triazole(PSN-II-23)

To a solution of3-(naphthalen-1-ylmethyl)-5-(phenylthio)-4-(3-(1-trityl-1H-imidazol-4-yl)propyl)-4H-1,2,4-triazole(X) (250 mg, 0.37 mmol) in ACN (6 mL) and methanol (20 mL) was addeddiethylamine (8 □L, 0.08 mmol). To this mixture was added a solution ofoxone (500 mg, 0.81 mmol) in H₂O (12 mL). The resulting reaction mixturewas heated to 65° C. for 5 h. The reaction was cooled and partitionedwith EtOAc (200 mL) and sat. NaHCO₃ (200 mL). The layers were separatedand the aqueous was extracted (5×50 mL) with EtOAc. The combinedextracts were dried (Na₂SO₄), filtered and concentrated. Purification byflash chromatography (10:1 CHCl3/MeOH) afforded 37 mg (22% yield) ofcompound X as a colorless glass: ¹H NMR (400 MHz, CD₃OD) □ 8.04-7.98 (m,1H), 7.96 (dt, J=8.1, 1.1 Hz, 2H), 7.90-7.83 (m, 1H), 7.82-7.70 (m, 2H),7.66-7.59 (m, 2H), 7.54-7.44 (m, 3H), 7.35 (dd, J=8.3, 7.0 Hz, 1H), 7.11(dd, J=7.0, 1.1 Hz, 1H), 6.65 (s, 1H), 4.21-4.09 (m, 2H), 2.44 (t, J=7.1Hz, 2H), 1.70 (quint., J=7.1 Hz, 2H). ¹³C NMR (100 MHz, CD₃OD) Q 157.08,153.13, 138.58, 135.01, 134.15, 131.71, 130.35, 129.57, 128.61, 128.25,126.73, 125.88, 125.18, 123.12, 44.92, 29.47, 28.34, 23.24. LCMS (25-95%acetonitrile in 0.05% TFA over 10 minutes) retention time=6.00 min, ESIm/z=458 [M+H]⁺. HRMS (ESI Q-TOF) m/z=458.1638 (458.1645 calc'd forC₂₅H₂₄N₅O₂S, [M+H]⁺).

Example 3: Radioligand Binding Assay

Competitive radioligand binding experiments were performed usingMEMBRANE TARGET Systems (Perkin-Elmer, Boston, Mass.) for humansomatostatin receptors: SSTR1 (ES-520-M4000A), SSTR2A (ES-521-M400UA),SSTR3 (ES523-M400UA), SSTR4 (ES-524-M400UA) and SSTR5 (ES-522-M400UA)receptors. (See Table 1). Respective membrane receptor preparations wereprepared in assay buffer (25 mM HEPES, 10 mM MgCI₂, 1 mM CaCI₂, 0.5%BSA, pH=7.4) at a 1:150 dilution. Binding assays were performed using1251-Tyr-SRIF 14 (Perkin-Elmer, NEX 3890) dissolved in 1 mM HCI. Bindingassays were performed in triplicate for each concentration of ligand ina total volume of 200 μL radioligand (25 μL ligand, 25 μL radioligand,150 μL receptors) and incubated at room temperature for 90 minutes usinga shaking table. Binding was terminated by filtration through GF/B glassfiber filters that were presoaked in 0.5% polyethyleneimine for aminimum of 4 hours. Filters were washed 9× with 1000 μL ice cold washbuffer (50 mM Tris-HCI, pH=7.4, 0.2% BSA). Filters were scored,transferred into plastic test tubes and counted in a gamma counter(Wizard2, Perkin-Elmer). Determination of the Ki for each compound wasperformed using non-linear regression with GraphPad PRISM-5 software(GraphPad Software, Inc., La Jolla, Calif.).

TABLE 1 Competitive Radioligand Binding Data Compound SST1 (nM) SST2(nM) SST3 (nM) SST4 (nM) SSTS (nM) SST1 SST2 SST3 SST4 SST5 Compound(nM) (nM) (nM) (nM) (nM) BN-VI-61 >10000 >10000 >10000 7.738 >100009.325 BN-VI-56 6929 >10000 >10000 5.087 >10000 7.775 BN-VI-62 >1000037.52 47.28 BN-VI-87 >10000 447.7 BN-VI-89 6975 51.70 BN-VI-975309 >10000 >10000 3.20 >10000 SM-I-26 >10000 >10000 >10000 11.95 >1000012.80 SM-I-29 >10000 267.2 SM-I-38 >10000 >10000 >10000 12.43 >10000SM-I-50 4744 >10000 >10000 5.54 >10000 SM-I-55 >10000 >10000 >1000016.20 >10000 SM-I-60 3172 >10000 6989 40.37 >10000 SM-I-76 >10000 11.02SM-I-92 >10000 6.979 MM-I-17 >10000 >10000 >10000 21.47 >10000MM-I-21 >10000 >10000 >10000 39.53 >10000 MM-I-26 >10000 945.3 MM-I-364076 >10000 14.91 MM-I-43 >10000 36.60 MM-I-53 >10000 386.6MM-I-63 >10000 30.33 MM-I-66 587.6 >10000 2335 0.8250 >10000 0.8383MM-I-72 660.7 >10000 1.023 MM-I-83 2080 1.036 MM-I-87 3278 0.6726MM-I-89 >10000 2.966 SK-I-16 >10000 1.719 SK-I-22 7693 1.422 SK-I-232576 >10000 >10000 2.219 >10000 SK-I-25 >10000 1.695 SK-I-53 17167103 >10000 3.107 >10000 SK-I-55 1032 5,434 >10000 2.791 >10000 SK-I-561011 >10000 >10000 3.326 >10000 SK-I-57 365.3 1693 1129 1.759 >10000SK-I-91 468.0 3,969 >10000 0.9025 >10000 SK-I-105 1,080 5,304 >100005.133 >10000 SK-I-119 4,336 >10000 >10000 57.05 >10000 SK-I-124 97.82639.7 1736 0.7070 >10000 AH-1-33 >10000 92.84 AH-1-40 >10000 90.18AH-1-41 >10000 78.80 AH-1-47 4076 >10000 2414 31.05 >10000 (3435-4835)AH-1-75 >10000 1347 AH-1-81 >10000 213.6 AH-1-84 >10000 959.2AH-1-86 >10000 >10000 76.14 >10000 AH-1-94 >10000 20.87 >10000AH-1-96 >10000 563.3 AH.1.102 >10000 916.2 AH.1.109 >10000 26.37AH.1.112 >10000 16.18 AH.1.116 >10000 53.12 AH.1.118 >10000 19.30AH.2.126 >10000 775.7 AH.2.130 >10000 306.0 AH.2.131 >10000 140.8AH.2.132 2134 >10000 >10000 27.32 >10000 AH.2.145 >10000 59.32AH.2.160 >10000 326.8 AH.2.162 2250 >10000 >10000 16.51 >10000 AH.2.1651644 >10000 >10000 13.76 >10000 MS.1.22 4645 7695 >10000 129.6 >10000MS.1.27 >10000 >10000 >10000 152.2 >10000 MS.1.30 6,633 >10000 >10000151.8 >10000 AH.2.178 >10000 12.29 AH.2.182 2451 8094 5934 8.390 >10000AH.2.199 >10000 80.75 AH.2.206 301.4 596.7 SK-I-128 314.6 2937 >100000.6318 >10000 SK-I-130 732.7 3918 5553 3.723 >10000 SK-I-132 655.7 28762912 0.6464 >10000

Example 4: Activity Assays

Measurement of forskolin stimulated inhibition of cAMP was performed viatime-resolved fluorescence resonance energy transfer (TR-FRET) LANCEassay (AD0262, PerkinElmer Life Science, Inc., Boston Mass.).Recombinant Chinese hamster ovary (CHO-Ki) cells expressing humansomatostatin SSTR4 cells (ES-524-CF, PerkinElmer Life Science, Inc.,Boston Mass.) were thawed (37° C.), resuspended in 10 mL 187 Hanks'balanced salt solution no phenol red (HIBSS, Invitrogen, CarlsbadCalif.), and then centrifuged (150×g, 5 minutes). Cellular pelletresuspended in stimulation buffer containing HIBSS 1×, HEPES 5 mM,Protease free BSA 0.1% (PerkinElmer), and 3-Isobutyl-1-methylxanthine0.5 mM (pH 7.4) and seeded in 96-well plates at 4000 cells/well. LANCEcAMP assay was performed per manufacture instruction with assessment ofrespective compound, somatostatin-28 (Sigma-Aldrich Co., St. Louis, Mo.)as control agonist, against 5 μM forskolin, performed in triplicateacross concentration curve. Fluorescence signal was measured at 20 hours(excitation 340 nm and emission 665 nm, 400-μs delay) via TR-FRET(FLUOSTAR Omega-F, BMG Labtech, Inc., Cary, N.C.). Data was calculatedvia GraphPad PRISM-5 software.

Measurement of β-arrestin was conducted with use of the PATHHUNTEReXpress SSTR4 CHO-K1 β-Arrestin GPCR Assay (93-0308E2, Discover Rx).PathHunter EXPRESS β-Arrestin SSTR4 cells (CHO-K1, DiscoverX) areengineered to co-express the PROLINK (PK) and the Enzyme Acceptor (EA)tagged β-Arrestin. Activation of the SSTR4-PK induces β-Arrestin-EArecruitment, forcing complementation of the two β-galactosidase enzymefragments (EA and PK). Cells were thawed and diluted in cell-platingreagent, with subsequent plating in 96-well plate (100 μL/well) andincubated at 37° C./5% CO₂ for 48 hours. Serial dilutions of controlcurve (somatostatin-28, Sigma-Aldrich Co., St. Louis, Mo.) andcompound(s) being tested are added after 48 hours incubation. Aftersubsequent incubation with control/compounds for 90 minutes, detectionreagent is added followed by a 1 hour incubation. The resultingfunctional enzyme hydrolyzes substrate to generate a chemiluminescentsignal which is measured (FLUOSTAR Omega-F, BMG Labtech, Inc., Cary,N.C.). Data was calculated via GraphPad PRISM-5 software.

TABLE 2 Activity Assay Data EC₅₀ cAMP Compound (nM) BN-VI-61 15.62BN-VI-56 7.264 BN-VI-62 19.28 BN-VI-87 691.7 BN-VI-89 17.01 BN-VI-976.083 SM-1-26 16.51 23.48 SM-1-38 21.02 SM-1-50 4.35 SM-1-55 8.811SM-1-60 21.31 SM-1-76 10.69 SM-1-92 22.72 MM-I-17 17.31 MM-I-21 28.88MM-I-36 54.96 MM-I-43 98.42 MM-I-53 254.5 MM-I-63 75.75 MM-I-66 0.5851MM-I-72 3.324 MM-I-83 0.2756 MM-I-87 0.2495 MM-I-89 2.799 SK-I-16 1.756SK-I-22 1.280 SK-I-23 7.271 SK-I-25 2.032 SK-I-53 5.972 SK-I-55 6.021SK-I-56 5.630 SK-I-57 1.003 SK-I-91 3.173 SK-I-105 6.650 SK-I-119 77.72SK-I-124 0.7253 AH-1-33 130.2 AH-1-40 213.5 AH-1-41 35.00 AH-1-47 85.19AH-1-81 969.9 AH-1-86 104.6 AH-1-94 21.89 AH-1-96 3778 AH.1.109 38.49AH.1.112 25.17 AH.1.116 44.02 AH.1.118 52.77 AH.2.126 1128 AH.2.130 2708AH.2.131 142.8 AH.2.132 89.27 AH.2.145 46.94 AH.2.160 1399 AH.2.16213.96 AH.2.165 8.410 MS.1.22 165.5 MS.1.27 612.8 MS.1.30 289.6 AH.2.17817.46 AH.2.182 10.00 AH.2.199 143.9 AH.2.206 301.4 SK-I-128 0.6186SK-I-130 3.086 SK-I-132 0.9915

What is claimed is:
 1. A compound comprising Formula (II):

wherein

are independently a single bond or is absent; A is C(H) or N; B and Care independent C(H), N, N(H), O, or S, provided that when B or C isC(H) or N,

is a single bond, and when B or C is N(H), O, or S,

is absent; D is S, O, NR¹⁶, P, sulfone, or sulfoxide; R¹ and R⁷ areindependently hydrogen, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted cycloalkyl or substituted or unsubstitutedfused ring system; R² is substituted or unsubstituted C₁-C₆ alkyl; R³,R⁴, and R⁵ are independently hydrogen, F, Cl, Br, I, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted amine, sulfoxide, sulfone, thiosulfinate, thiosulfonate,thioamide, sulfimide, sulfoximide, sulfonediimine, or sulfur halide. R⁶and R⁸ are independently hydrogen, F, Cl, Br, I, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedcycloalkyl; R⁹ and R¹⁵ are independently substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl;and R¹⁶ is hydrogen, C₁-C₆ alkyl, aryl, or benzyl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein

are each a single bond and A, B, and C are N.
 3. The compound of claim1, wherein D is S, sulfone, or sulfoxide.
 4. The compound of claim 1,wherein R⁹ is a bond.
 5. The compound of claim 1, wherein R¹⁵ isunsubstituted C₁-C₃ alkyl.
 6. The compound of claim 1, wherein R⁶ and R⁸are independently hydrogen or substituted or unsubstituted C₁-C₃ alkyl.7. The compound of claim 1, wherein R¹ and R⁷ are independentlysubstituted or unsubstituted aryl or substituted or unsubstituted fusedring system.
 8. The compound of claim 7, wherein R¹ is substituted orunsubstituted fused ring system.
 9. The compound of claim 8, wherein R¹is substituted or unsubstituted indole, substituted or unsubstitutednaphthalene, or substituted or unsubstituted quinolone.
 10. The compoundof claim 7, wherein R⁷ is substituted or unsubstituted aryl orsubstituted or unsubstituted indole.
 11. The compound of claim 10,wherein R⁷ is

and R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ is independently hydrogen, F, Cl, Br, I,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted amine, sulfoxide, sulfone, thiosulfinate,thiosulfonate, thioamide, sulfimide, sulfoximide, sulfonediimine, orsulfur halide.
 12. The compound of claim 11, wherein R¹⁰, R¹¹, R¹², R¹³,and R¹⁴ is independently hydrogen, F, Cl, Br, I, CF₃, OCH₃, NO₂,OCH₂(C₆H₄), C₆H₄, SO₂CH₃, or OCF₃.
 13. The compound of claim 1, whereinR² is substituted or unsubstituted C₁-C₃ alkyl.
 14. The compound ofclaim 1, wherein R³, R³, and R⁴ are independently hydrogen, F, Cl, Br,I, substituted or unsubstituted alkyl.
 15. The compound of claim 14,wherein R³, R³, and R⁴ are hydrogen.
 16. The compound of claim 1,wherein R¹⁵ is unsubstituted C₁-C₆ alkyl.
 17. The compound of claim 1,wherein the compound is selected from the group consisting of:


18. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


19. A method for the treatment of pain or inflammation which comprisesadministering to a subject in need thereof a therapeutically effectiveamount of a compound according to claim
 1. 20. A pharmaceuticalcomposition containing a compound according to claim 1 and apharmaceutically acceptable carrier.